bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigenic and Genetic Evolution of Equine Influenza A (H3N8) Virus from 1968 to 2007
Authors: Lewis N. S. , Daly J. M. , Russell C. A. , Horton D. L. , Skepner E. , Bryant N. A. , Burke D. F. , Rash A. S. , Wood J. L. N. , Chambers T. M. , Fouchier R. A. M. , Mumford J. A. , Elton D. M. , Smith D. J. 
Published: September 2011

ABSTRACT
Equine influenza virus is a major respiratory pathogen in horses, and outbreaks of disease often lead to substantial disruption to and economic losses for equestrian industries. The hemagglutinin (HA) protein is of key importance in the control of equine influenza because HA is the primary target of the protective immune response and the main component of currently licensed influenza vaccines. However, the influenza virus HA protein changes over time, a process called antigenic drift, and vaccine strains must be updated to remain effective. Antigenic drift is assessed primarily by the hemagglutination inhibition (HI) assay. We have generated HI assay data for equine influenza A (H3N8) viruses isolated between 1968 and 2007 and have used antigenic cartography to quantify antigenic differences among the isolates. The antigenic evolution of equine influenza viruses during this period was clustered: from 1968 to 1988, all isolates formed a single antigenic cluster, which then split into two cocirculating clusters in 1989, and then a third cocirculating cluster appeared in 2003. Viruses from all three clusters were isolated in 2007. In one of the three clusters, we show evidence of antigenic drift away from the vaccine strain over time. We determined that a single amino acid substitution was likely responsible for the antigenic differences among clusters.
Hepatitis C Virus-Induced Cancer Stem Cell-Like Signatures in Cell Culture and Murine Tumor Xenografts
Authors: Ali Naushad , Allam Heba , May Randal , Sureban Sripathi M. , Bronze Michael S. , Bader Ted , Umar Shahid , Anant Srikant , Houchen Courtney W. 
Published: September 2011

ABSTRACT

Hepatitis C virus (HCV) infection is a prominent risk factor for the development of hepatocellular carcinoma (HCC). Similar to most solid tumors, HCCs are believed to contain poorly differentiated cancer stem cell-like cells (CSCs) that initiate tumorigenesis and confer resistance to chemotherapy. In these studies, we demonstrate that the expression of an HCV subgenomic replicon in cultured cells results in the acquisition of CSC traits. These traits include enhanced expression of
d
oublecortin and
CaM
k
inase-
l
ike-1 (DCAMKL-1), Lgr5, CD133, α-fetoprotein, cytokeratin-19 (CK19), Lin28, and c-Myc. Conversely, curing of the replicon from these cells results in diminished expression of these factors. The putative stem cell marker DCAMKL-1 is also elevated in response to the overexpression of a cassette of pluripotency factors. The DCAMKL-1-positive cells isolated from hepatoma cell lines by fluorescence-activated cell sorting (FACS) form spheroids in Matrigel. The HCV RNA abundance and NS5B levels are significantly reduced by the small interfering RNA (siRNA)-led depletion of DCAMKL-1. We further demonstrate that HCV replicon-expressing cells initiate distinct tumor phenotypes compared to the tumors initiated by parent cells lacking the replicon. This HCV-induced phenotype is characterized by high-level expression/coexpression of DCAMKL-1, CK19, α-fetoprotein, and active c-Src. The results obtained by the analysis of liver tissues from HCV-positive patients and liver tissue microarrays reiterate these observations. In conclusion, chronic HCV infection appears to predispose cells toward the path of acquiring cancer stem cell-like traits by inducing DCAMKL-1 and hepatic progenitor and stem cell-related factors. DCAMKL-1 also represents a novel cellular target for combating HCV-induced hepatocarcinogenesis.
EGFR and KRAS quality assurance schemes in pathology: generating normative data for molecular predictive marker analysis in targeted therapy
Authors: Thunnissen Erik , Bovée Judith V M G , Bruinsma Hans , van den Brule Adriaan J C , Dinjens Winand , Heideman Daniëlle A M , Meulemans Els , Nederlof Petra , van Noesel Carel , Prinsen Clemens F M , Scheidel Karen , van de Ven Peter M , de Weger Roel , Schuuring Ed , Ligtenberg Marjolijn 
Published: September 2011

IntroductionThe aim of this study was to compare the reproducibility of epidermal growth factor receptor (EGFR) immunohistochemistry (IHC),EGFRgene amplification analysis, andEGFRandKRASmutation analysis among different laboratories performing routine diagnostic analyses in pathology in The Netherlands, and to generate normative data.MethodsIn 2008, IHC, in-situ hybridisation (ISH) forEGFR, and mutation analysis forEGFRandKRASwere tested. Tissue microarray sections were distributed for IHC and ISH, and tissue sections and isolated DNA with known mutations were distributed for mutation analysis. In 2009, ISH and mutation analysis were evaluated. False-negative and false-positive results were defined as different from the consensus, and sensitivity and specificity were estimated.ResultsIn 2008, eight laboratories participated in the IHC ring study. In only 4/17 cases (23%) a consensus score of ≥75% was reached, indicating that this analysis was not sufficiently reliable to be applied in clinical practice. ForEGFRISH, andEGFRandKRASmutation analysis, an interpretable result (success rate) was obtained in ≥97% of the cases, with mean sensitivity ≥96% and specificity ≥95%. For small sample proficiency testing, a norm was established defining outlier laboratories with unsatisfactory performance.ConclusionsThe result of EGFR IHC is not a suitable criterion for reliably selecting patients for anti-EGFR treatment. In contrast, molecular diagnostic methods forEGFRandKRASmutation detection andEGFRISH may be reliably performed with high accuracy, allowing treatment decisions for lung cancer.
Replacement of conventional HIV testing with rapid testing: mathematical modelling to predict the impact on further HIV transmission between men
Authors: Wilson David P , Fairley Christopher K , Sankar Daniel , Williams Henrietta , Keen Phillip , Read Tim R H , Chen Marcus Y 
Published: September 2011

BackgroundRapid HIV testing is not permitted in Australia at the point of care. The authors evaluate the expected net effect of rapid HIV testing compared with standard serology diagnostic tests in terms of onward HIV transmission.MethodsThe authors used data for 174 men who had sex with men testing HIV-positive at the Melbourne Sexual Health Centre, Australia, in an agent-based mathematical model. Time of diagnosis is simulated according to conventional enzyme immunoassays or rapid HIV tests, with different window periods. The authors calculated the expected number of additional/averted transmissions due to missed or earlier diagnoses.ResultsFourth generation rapid tests were simulated to miss ∼2–3% of diagnoses compared with conventional fourth generation enzyme immunoassay tests. However, in the remaining 97–98% of cases the rapid test would result in earlier detection of HIV. Overall, the rapid test would reduce time to patients receiving results by a median of ∼12 days. Assuming no changes in testing rates, the introduction of rapid testing diagnostic technologies would prevent one in every 2000–5000 HIV transmissions compared with the conventional diagnostic test.ConclusionsRapid tests would have a marginal benefit in reducing HIV transmission between men compared with conventional tests under assumptions of no changes in testing frequencies.
IDIBELL Cancer Conference on Metastasis and Angiogenesis
Authors: Carmona F. Javier , Esteller Manel 
Published: September 2011

Abstract
The IDIBELL Cancer Conference (ICC) on Metastasis and Angiogenesis was held in Barcelona, Spain, on May 26–27, 2011. The program content was developed by Dr. Manel Esteller, director of the Cancer Epigenetics and Biology Program (PEBC-IDIBELL), Dr. Oriol Casanovas and Dr. Francesc Viñals Canals of the Catalan Institute of Oncology (ICO-IDIBELL), and Dr. Danny R. Welch from the University of Kansas Cancer Center. The topics discussed during the meeting included the latest advances in epigenetic control of metastasis and tumor cell invasion, and molecular mechanisms of angiogenesis and tumoral angiogenesis, and were presented by invited keynote speakers. One issue that recurred throughout the meeting was the increased appreciation of tumor–stromal/microenvironment interactions and how the tumor cells respond to these signals in the cancer dissemination process. Cancer Res; 71(19); 6097–101. ©2011 AACR.
TNF-α Promotes c-REL/ΔNp63α Interaction and TAp73 Dissociation from Key Genes That Mediate Growth Arrest and Apoptosis in Head and Neck Cancer
Authors: Lu Hai , Yang Xinping , Duggal Praveen , Allen Clint T. , Yan Bin , Cohen Jonah , Nottingham Liesl , Romano Rose-Anne , Sinha Satrajit , King Kathryn E. , Weinberg Wendy C. , Chen Zhong , Van Waes Carter 
Published: September 2011

AbstractInflammation-induced activation of proto-oncogenic NF-κB/REL and dysfunction of tumor suppressor TP53/p63/p73 family transcription factors are key events in cancer progression. How inflammatory signaling coordinates dysregulation of these two transcription factor families during oncogenesis remains incompletely understood. Here, we observed that oncoprotein c-REL and tumor suppressor TAp73 are coexpressed and complex with ΔNp63α in the nucleus of a subset of head and neck squamous cell carcinoma (HNSCC) cell lines with mutant (mt)TP53. TNF-α, a proinflammatory cytokine, promoted c-REL nuclear translocation, c-REL/ΔNp63α interaction, and dissociation of TAp73 from ΔNp63α and the nucleus to the cytoplasm, whereas c-REL siRNA knockdown attenuated this effect. Overexpression of c-REL or a c-REL κB-site DNA-binding mutant enhanced protein interaction with ΔNp63α and TAp73 dissociation, implicating c-REL/ΔNp63α-specific interactions in these effects. We discovered that TNF-α or genetic alteration of c-REL expression inversely modulates ΔNp63α/TAp73 interactions on distinct p63 DNA-binding sites, including those for key growth arrest and apoptotic genes p21WAF1, NOXA, and PUMA. Functionally, c-REL repressed these genes and the antiproliferative effects of TNF-α or TAp73. Conversely, c-REL siRNA depletion enhanced TAp73 promoter interaction and expression of genes mediating growth arrest and apoptosis. Similar to TNF-α–treated HNSCC lines, human HNSCC tumors and hyperplastic squamous epithelia of transgenic mice overexpressing ΔNp63α that exhibit inflammation also show increased nuclear c-REL/ΔNp63α and cytoplasmic TAp73 localization. These findings unveil a novel and reversible dynamic mechanism whereby proinflammatory cytokine TNF-α–induced c-REL/ΔNp63α interactions inactivate tumor suppressor TAp73 function, promoting TNF-α resistance and cell survival in cancers with mtTP53. Cancer Res; 71(21); 6867–77. ©2011 AACR.
Synergistic Activity of Fenretinide and the Bcl-2 Family Protein Inhibitor ABT-737 against Human Neuroblastoma
Authors: Fang Hua , Harned Theresa M. , Kalous Ondrej , Maldonado Vanessa , DeClerck Yves A. , Reynolds C. Patrick 
Published: September 2011

Abstract
Purpose: Fenretinide (4-HPR) is a cytotoxic retinoid with minimal systemic toxicity that has shown clinical activity against recurrent high-risk neuroblastoma. To identify possible synergistic drug combinations for future clinical trials, we determined whether ABT-737, a small-molecule BH3-mimetic that inhibits most proteins of the antiapoptotic Bcl-2 family, could enhance 4-HPR activity in neuroblastoma.
Experimental Design: Eleven neuroblastoma cell lines were tested for the cytotoxic activity of 4-HPR and ABT-737 as single agents and in combination using the DIMSCAN fluorescence digital imaging cytotoxicity assay. The effect of these agents alone and in combination on mitochondrial membrane depolarization and apoptosis (by flow cytometry), cytochrome c release, caspases, Bax-α, t-Bid, and Bak activation, and subcutaneous xenografts in nu/nu mice was also determined.
Results: Multilog synergistic cytotoxicity was observed for the drug combination in all of the 11 neuroblastoma cell lines tested, including MDR lines and those insensitive to either drug as single agents. 4-HPR + ABT-737 induced greater mitochondrial membrane depolarization and mitochondrial cytochrome c release, greater activation of caspases, Bax-α, t-Bid, and Bak, and a higher level of apoptosis than either drug alone. In vivo, 4-HPR + ABT-737 increased the event-free survival of the MDR human neuroblastoma line CHLA-119 implanted subcutaneously in nu/nu mice (194.5 days for the combination vs. 68 days for ABT-737 and 99 days for 4-HPR).
Conclusion: Thus, the combination of 4-HPR with a BH3-mimetic drug warrants clinical trials in recurrent neuroblastoma. Clin Cancer Res; 17(22); 7093–104. ©2011 AACR.
Crystal Structure of a Multidomain Human p53 Tetramer Bound to the Natural CDKN1A (p21) p53-Response Element
Authors: Emamzadah Soheila , Tropia Laurence , Halazonetis Thanos D. 
Published: September 2011

Abstract
The p53 tumor suppressor protein is a sequence-specific DNA-binding transcription factor. Structures of p53 bound to DNA have been described, but, so far, no structure has been determined of p53 bound to a natural p53-response element. We describe here the structure of a human p53 homotetramer encompassing both the DNA-binding and homo-oligomerization domains in complex with the natural p53-response element present upstream of the promoter of the CDKN1A (p21) gene. Similar to our previously described structures of human p53 tetramers bound to an artificial consensus DNA site, p53 DNA binding proceeds via an induced fit mechanism with loops L1 of two subunits adopting recessed conformations. Interestingly, the conformational change involving loop L1 is even more extreme than the one previously observed with the artificial consensus DNA site. In fact, the previously determined loop L1 conformation seems to be a transition intermediate between the non–DNA-bound and CDKN1A-bound states. Thus, the new structure further supports our model that recognition of specific DNA by p53 is associated with conformational changes within the DNA-binding domain of p53. Mol Cancer Res; 9(11); 1493–9. ©2011 AACR.
Thrombin generation and activated protein C resistance in the absence of factor V Leiden correlates with the risk of recurrent venous thromboembolism in women aged 18–65 years
Authors: Tchaikovski Svetlana , Holmström Margareta , Rosing Jan , Bremme Katarina , Lärfars Gerd , Sonnevi Kristina 
Published: September 2011

SummaryIdentification of patients at high risk of recurrence after a first event of venous thromboembolism (VTE) remains difficult. Resistance to activated protein C (APC) is a known risk factor for VTE, but data on the risk of recurrence is controversial. We wanted to investigate whether APC resistance in the absence of factor V Leiden, determined with global coagulation test such as the thrombin generation assay, could be used as a marker for increased risk of recurrent VTE among women 18–65 years old after a first event of VTE. In a cohort of 243 women with a first event of VTE, plasma was collected after discontinuation of anticoagulant treatment and the patients were followed up for 46 months (median). Thrombin generation was measured via calibrated automated thrombography, at 1 pM and 10 pM of tissue factor (TF). In women without factor V Leiden (n=117), samples were analysed in the absence and in the presence of APC. Increase in ETP (endogenous thrombin potential) and peak height analysed in the presence of APC correlated significantly with higher risk of recurrence. At 1 pM, peak height correlated with increased risk of recurrence. In conclusion, high thrombin generation in the presence of APC, in women after a first event of VTE is indicative for an increased risk of a recurrence. We also found that thrombin generation at low TF (1 pM) is correlated with the risk of recurrence. Our data suggest that APC resistance in the absence of factor V Leiden is a risk factor for recurrent VTE.
Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation
Authors: Wolfs Ine , Donners Marjo , de Winther Menno 
Published: September 2011

SummaryThe phenotype of macrophages in atherosclerotic lesions can vary dramatically, from a large lipid laden foam cell to a small inflammatory cell. Classically, the concept of macrophage heterogeneity discriminates between two extremes called either pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Polarisation of plaque macrophages is predominantly determined by the local micro-environment present in the atherosclerotic lesion and is rather more complex than typically described by the M1/M2 paradigm. In this review we will discuss the role of various polarising factors in regulating the phenotypical state of plaque macrophages. We will focus on two main levels of phenotype regulation, one determined by differentiation factors produced in the lesion and the other determined by T-cell-derived polarising cytokines. With foam cell formation being a key characteristic of macrophages during atherosclerosis initiation and progression, these polarisation factors will also be linked to lipid handling of macrophages.
Influence of the morphology of thermoplastic elastomers on the properties of bitumen composites
Authors: Dimonie Doina , Dimonie Mihai , Iliescu Simona , Pavel Marcel , Manoiu Dumitru , Fierascu Radu , Dumitriu Irina , Petrea Celina , Socoteanu Radu 
Published: September 2011

Bitumen properties may be successfully modified if the polymeric modifiers have the ability to control the elastic and plastic properties within wide temperature ranges of −30/−40°C to +45/+60°C. The article presents a study on the ability of two thermoplastic elastomers, thermoplastic block co-polymer styrene–styrene butadiene (SBS) and the co-polymer ethylene–vinyl acetate (EVA), to be used in obtaining polymer bitumen composites with controlled properties. The elastic and plastic properties of the bitumen composites can be more easily controlled if these composites are modified with SBS. This thermoplastic elastomer is characterized by an optimum ratio between soft domains of amorphous polybutadiene and rigid ones of those represented by the thermoplastic blocks of polystyrene.
A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain
Authors: Ahmedzai Sam H , Nauck Friedemann , Bar-Sela Gil , Bosse Björn , Leyendecker Petra , Hopp Michael 
Published: September 2011

Objective: An examination of whether oxycodone/naloxone prolonged-release tablets (OXN PR) can improve constipation and maintain analgesia, compared with oxycodone prolonged-release tablets (OxyPR) in patients with moderate/severe cancer pain. Methods: Randomized, double-blind, active-controlled, double-dummy, parallel-group study in which 185 patients were randomized to receive up to 120 mg/day of OXN PR or OxyPR over 4 weeks. Efficacy assessments included Bowel Function Index (BFI), Brief Pain Inventory Short-Form (BPI-SF), laxative and rescue medication use. Quality of life (QoL) and safety assessments were conducted. Results: After 4 weeks, mean BFI score was significantly lower with OXN PR; mean total laxative intake was 20% lower with OXN PR. Mean BPI-SF scores were similar for both treatments and the average rate of analgesic rescue medication use was low and comparable. QoL assessments were stable and comparable with greater improvements in constipation-specific QoL assessments with OXN PR. Overall, rates of adverse drug reactions were similar. Conclusions: OXN PR provides superior bowel function in cancer pain patients, compared with OxyPR, without compromising analgesic efficacy or safety. This study confirms that OXN PR is well tolerated and efficacious in cancer pain patients and results are in line with those seen in non-malignant pain patients.
Effect of Graft Height Mismatch on Contact Pressures With Osteochondral Grafting of the Talus
Authors: Latt L. Daniel , Glisson Richard R. , Montijo Harvey E. , Usuelli Federico G. , Easley Mark E. 
Published: September 2011

Background: Osteochondral allograft transplantation is technically demanding. It is not always possible to place the surface of the graft perfectly flush with the surrounding cartilage. One must often choose between placing at least some portion of the surface of the graft slightly elevated or recessed. The effect of this choice on joint contact pressure is unknown. Purpose: This study was undertaken to determine the effect of graft height mismatch on joint contact pressure in the ankle. Study Design: Controlled laboratory study. Methods: Ten human cadaveric ankles underwent osteochondral grafting by removal then replacement of an osteochondral plug. Six conditions were tested: intact, graft flush, graft elevated 1.0 mm, graft elevated 0.5 mm, graft recessed 0.5 mm, and graft recessed 1.0 mm. Joint contact pressures were measured with a Tekscan sensor while loads of 200 N, 400 N, 600 N, and 800 N were sequentially applied. Results: The peak contact pressure at the graft site for the flush condition was not significantly different from the intact condition for either medial or lateral lesions. In contrast, peak pressure on the opposite facet of the talar dome was significantly increased during the flush condition for the medial but not the lateral grafts. Elevated grafts experienced significantly increased contact pressures, whereas recessed grafts experienced significantly decreased pressures. These changes were greater for lateral than for medial lesions. Reciprocal changes in joint contact pressures were found on the opposite facet of the talus with elevated grafts on the lateral side and recessed grafts on the medial side. Conclusion: Flush graft placement can restore near-normal joint contact pressure. Elevated graft placement leads to significant increases in joint contact pressure at the graft site. Recessed graft placement leads to a transfer of pressure from the graft site to the opposite facet of the talus. Clinical Relevance: Osteochondral grafts in the talus should be placed flush if possible or else slightly recessed.
Designing and implementing telemonitoring for early detection of deterioration in chronic disease: Defining the requirements
Authors: Peirce Susan C. , Hardisty Alex R. , Preece Alun D. , Elwyn Glyn 
Published: September 2011

Patients with chronic disease may suffer frequent acute deteriorations and associated increased risk of hospitalisation. Earlier detection of these could enable successful intervention, improving patients’ well-being and reducing costs; however, current telemonitoring systems do not achieve this effectively. We conducted a qualitative study using stakeholder interviews to define current standards of care and user requirements for improved early detection telemonitoring. We determined that early detection is not a concept that has informed technology or service design and that telemonitoring is driven by the available technology rather than by users’ needs. We have described a set of requirements questions to inform the design and implementation of telemonitoring systems and suggested the research needed to develop successful early detection telemonitoring. User-centred design and genuine interdisciplinary approaches are needed to create solutions that are fit for purpose, sustainable and address the real needs of patients, clinicians and healthcare organisations.