bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flexibility of the Head-Stalk Linker Domain of Paramyxovirus HN Glycoprotein Is Essential for Triggering Virus Fusion
Authors: Adu-Gyamfi Emmanuel , Kim Lori S. , Jardetzky Theodore S. , Lamb Robert A. 
Published: August 2016

ABSTRACT

The
Paramyxoviridae
comprise a large family of enveloped, negative-sense, single-stranded RNA viruses with significant economic and public health implications. For nearly all paramyxoviruses, infection is initiated by fusion of the viral and host cell plasma membranes in a pH-independent fashion. Fusion is orchestrated by the receptor binding protein hemagglutinin-neuraminidase (HN; also called H or G depending on the virus type) protein and a fusion (F) protein, the latter undergoing a major refolding process to merge the two membranes. Mechanistic details regarding the coupling of receptor binding to F activation are not fully understood. Here, we have identified the flexible loop region connecting the bulky enzymatically active head and the four-helix bundle stalk to be essential for fusion promotion. Proline substitution in this region of HN of parainfluenza virus 5 (PIV5) and Newcastle disease virus HN abolishes cell-cell fusion, whereas HN retains receptor binding and neuraminidase activity. By using reverse genetics, we engineered recombinant PIV5-EGFP viruses with mutations in the head-stalk linker region of HN. Mutations in this region abolished virus recovery and infectivity. In sum, our data suggest that the loop region acts as a “hinge” around which the bulky head of HN swings to-and-fro to facilitate timely HN-mediate F-triggering, a notion consistent with the stalk-mediated activation model of paramyxovirus fusion.

IMPORTANCE
Paramyxovirus fusion with the host cell plasma membrane is essential for virus infection. Membrane fusion is orchestrated via interaction of the receptor binding protein (HN, H, or G) with the viral fusion glycoprotein (F). Two distinct models have been suggested to describe the mechanism of fusion: these include “the clamp” and the “provocateur” model of activation. By using biochemical and reverse genetics tools, we have obtained strong evidence in favor of the HN stalk-mediated activation of paramyxovirus fusion. Specifically, our data strongly support the notion that the short linker between the head and stalk plays a role in “conformational switching” of the head group to facilitate F-HN interaction and triggering.
Inhibition of Human Metapneumovirus Binding to Heparan Sulfate Blocks Infection in Human Lung Cells and Airway Tissues
Authors: Klimyte Edita M. , Smith Stacy E. , Oreste Pasqua , Lembo David , Dutch Rebecca Ellis 
Published: August 2016

ABSTRACTHuman metapneumovirus (HMPV), a recently discovered paramyxovirus, infects nearly 100% of the world population and causes severe respiratory disease in infants, the elderly, and immunocompromised patients. We previously showed that HMPV binds heparan sulfate proteoglycans (HSPGs) and that HMPV binding requires only the viral fusion (F) protein. To characterize the features of this interaction critical for HMPV binding and the role of this interaction in infection in relevant models, we utilized sulfated polysaccharides, heparan sulfate mimetics, and occluding compounds. Iota-carrageenan demonstrated potent anti-HMPV activity by inhibiting binding to lung cells mediated by the F protein. Furthermore, analysis of a minilibrary of variably sulfated derivatives ofEscherichia coliK5 polysaccharide mimicking the HS structure revealed that the highly O-sulfated K5 polysaccharides inhibited HMPV infection, identifying a potential feature of HS critical for HMPV binding. The peptide dendrimer SB105-A10, which binds HS, reduced binding and infection in an F-dependent manner, suggesting that occlusion of HS at the target cell surface is sufficient to prevent infection. HMPV infection was also inhibited by these compounds during apical infection of polarized airway tissues, suggesting that these interactions take place during HMPV infection in a physiologically relevant model. These results reveal key features of the interaction between HMPV and HS, supporting the hypothesis that apical HS in the airway serves as a binding factor during infection, and HS modulating compounds may serve as a platform for potential antiviral development.IMPORTANCEHuman metapneumovirus (HMPV) is a paramyxovirus that causes respiratory disease worldwide. It has been previously shown that HMPV requires binding to heparan sulfate on the surfaces of target cells for attachment and infection. In this study, we characterize the key features of this binding interaction using heparan sulfate mimetics, identify an important sulfate modification, and demonstrate that these interactions occur at the apical surface of polarized airway tissues. These findings provide insights into the initial binding step of HMPV infection that has potential for antiviral development.
Protocol of the PLeural Effusion And Symptom Evaluation (PLEASE) study on the pathophysiology of breathlessness in patients with symptomatic pleural effusions
Authors: Thomas Rajesh , Azzopardi Maree , Muruganandan Sanjeevan , Read Catherine , Murray Kevin , Eastwood Peter , Jenkins Sue , Singh Bhajan , Lee Y C Gary 
Published: August 2016

IntroductionPleural effusion is a common clinical problem that can complicate many medical conditions. Breathlessness is the most common symptom of pleural effusion of any cause and the most common reason for pleural drainage. However, improvement in breathlessness following drainage of an effusion is variable; some patients experience either no benefit or a worsening of their breathlessness. The physiological mechanisms underlying breathlessness in patients with a pleural effusion are unclear and likely to be multifactorial with patient-related and effusion-related factors contributing. A comprehensive study of the physiological and symptom responses to drainage of pleural effusions may provide a clearer understanding of these mechanisms, and may identify predictors of benefit from drainage. The ability to identify those patients whose breathlessness will (or will not) improve after pleural fluid drainage can help avoid unnecessary pleural drainage procedures, their associated morbidities and costs. The PLeural Effusion And Symptom Evaluation (PLEASE) study is a prospective study to comprehensively evaluate factors contributing to pleural effusion-related breathlessness.Methods and analysisThe PLEASE study is a single-centre prospective study of 150 patients with symptomatic pleural effusions that require therapeutic drainage. The study aims to identify key factors that underlie breathlessness in patients with pleural effusions and develop predictors of improvement in breathlessness following effusion drainage. Participants will undergo evaluation pre-effusion and post-effusion drainage to assess their level of breathlessness at rest and during exercise, respiratory and other physiological responses as well as respiratory muscle mechanics. Pre-drainage and post-drainage parameters will be collected and compared to identify the key factors and mechanisms that correlate with improvement in breathlessness.Ethics and disseminationApproved by the Sir Charles Gairdner Group Human Research Ethics Committee (HREC number 2014-079). Registered with the Australian New Zealand Clinical Trials Registry (ACTRN12616000820404). Results will be published in peer-reviewed journals and presented at scientific meetings.Trial registration numberACTRN12616000820404; Pre-results.
Interventions to improve hospital patient satisfaction with healthcare providers and systems: a systematic review
Authors: Davidson Karina W , Shaffer Jonathan , Ye Siqin , Falzon Louise , Emeruwa Iheanacho O , Sundquist Kevin , Inneh Ifeoma A , Mascitelli Susan L , Manzano Wilhelmina M , Vawdrey David K , Ting Henry H 
Published: August 2016

BackgroundMany hospital systems seek to improve patient satisfaction as assessed by the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys. A systematic review of the current experimental evidence could inform these efforts and does not yet exist.MethodsWe conducted a systematic review of the literature by searching electronic databases, including MEDLINE and EMBASE, the six databases of the Cochrane Library and grey literature databases. We included studies involving hospital patients with interventions targeting at least 1 of the 11 HCAHPS domains, and that met our quality filter score on the 27-item Downs and Black coding scale. We calculated post hoc power when appropriate.ResultsA total of 59 studies met inclusion criteria, out of these 44 did not meet the quality filter of 50% (average quality rating 27.8%±10.9%). Of the 15 studies that met the quality filter (average quality rating 67.3%±10.7%), 8 targeted the Communication with Doctors HCAHPS domain, 6 targeted Overall Hospital Rating, 5 targeted Communication with Nurses, 5 targeted Pain Management, 5 targeted Communication about Medicines, 5 targeted Recommend the Hospital, 3 targeted Quietness of the Hospital Environment, 3 targeted Cleanliness of the Hospital Environment and 3 targeted Discharge Information. Significant HCAHPS improvements were reported by eight interventions, but their generalisability may be limited by narrowly focused patient populations, heterogeneity of approach and other methodological concerns.ConclusionsAlthough there are a few studies that show some improvement in HCAHPS score through various interventions, we conclude that more rigorous research is needed to identify effective and generalisable interventions to improve patient satisfaction.
Engaging older patients in cardiovascular research: observational analysis of the ICON-1 study
Authors: Sinclair Hannah , Batty Jonathan A , Qiu Weiliang , Kunadian Vijay 
Published: August 2016

BackgroundAs a consequence of population ageing, the number of older patients presenting with acute coronary syndrome (ACS) is increasing. The historical underrepresentation of older patients in many pivotal ACS clinical trials undermines the practice of evidence-based medicine in this high-risk cohort. This study evaluates the feasibility of recruitment of older patients to a longitudinal, clinical study.MethodsThe study to Improve Cardiovascular Outcomes in high-risk patieNts with ACS (ICON-1) is an observational, prospective cohort study investigating predictors of poor outcome in older patients with ACS. All patients aged ≥75 years, referred to a tertiary cardiovascular centre in the North East of England for coronary angiography with a view to urgent percutaneous coronary intervention, were screened for inclusion. A screening log was prospectively maintained, and a detailed analysis was performed to identify the factors associated with recruitment and non-recruitment to ICON-1.ResultsOf the 629 patients screened over 34 months, 457 (72.7%) satisfied the a priori-defined study inclusion/exclusion criteria. Of those eligible to participate, 300 (68.5%) provided informed consent and were recruited to the study; 59 (13.5%) were unable to consent due to a lack of capacity or limitations in communication, and 79 patients (18.0%) declined to participate in the study. Those lacking adequate capacity to consent were older than those able to provide informed consent (83.0±4.7 vs 81.0±4.7 years, p=0.002). Women were more likely to decline than men (25.1% vs 10.0%, p<0.001).ConclusionsThe recruitment of patients was robust, comparing favourably to previous longitudinal studies within this age group. Although enrolling older people to research remains challenging, this cohort is enthusiastic to participate. The contribution of older patients must not be ignored, particularly in the setting of an ever-ageing population, in whom cardiovascular disease burden is high.Trial registration numberNCT01933581; Pre-results.
Timeliness of referral of children with new onset type 1 diabetes
Authors: Iyer Dhaara , Choudhary Deepak , Agwu Juliana Chizo 
Published: August 2016

ABSTRACTIntroductionType 1 diabetes (T1D) is characterised by autoimmune destruction of pancreatic β cells leading to insulin deficiency. Prompt referral to a specialist paediatric diabetes team (PDT) for insulin initiation and further management is important to prevent diabetic ketoacidosis (DKA), which remains the most common cause of death in this condition.ObjectiveThe aim was to study the timeliness of referrals from general practitioners (GPs) to PDT, of children suspected of having TID.MethodWe carried out a survey of the practice of GPs when they suspect TID in a young person, to investigate whether they recognised the need for urgent referral to PDT. In addition, we carried out retrospective case notes review of children diagnosed with diabetes mellitus between January 2005 and December 2014.Results111/300 (37%) of GPs replied to survey. Of these, 73/111 (65.8%) would have referred promptly to the PDT in accordance with National Guidelines. However, 34.2% would have taken an action that would have led to delay in referral to PDT. 96 children were diagnosed with TID during the audit period. There was a delay in referral in 35 (36.5%) children. 19/35 (54.3%) of these children presented with DKA. Mean duration of delay in presentation to the PDT was 1.8 days. In both survey and audit, the most common reason for delayed referral was GP attempting to confirm the diagnosis by undertaking further diagnostic tests.ConclusionsOur study has identified a modifiable reason for delayed referrals of children with TID.
An In Vivo Reporter to Quantitatively and Temporally Analyze the Effects of CDK4/6 Inhibitor-Based Therapies in Melanoma
Authors: Teh Jessica L.F. , Purwin Timothy J. , Greenawalt Evan J. , Chervoneva Inna , Goldberg Allison , Davies Michael A. , Aplin Andrew E. 
Published: August 2016

Abstract
Aberrant cell-cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinases 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma. CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib, was recently FDA approved for the treatment of estrogen receptor–positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF promote CDK4/6 activation, suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking. Here, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of antiapoptotic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts. These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma. Cancer Res; 76(18); 5455–66. ©2016 AACR.
Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma
Authors: Wolf Benita , Krieg Kathrin , Falk Christine , Breuhahn Kai , Keppeler Hildegard , Biedermann Tilo , Schmid Evi , Warmann Steven , Fuchs Joerg , Vetter Silvia , Thiele Dennis , Nieser Maike , Avci-Adali Meltem , Skokowa Yulia , Schöls Ludger , Hauser Stefan , Ringelhan Marc , Yevsa Tetyana , Heikenwalder Mathias , Kossatz-Boehlert Uta 
Published: August 2016

Abstract
Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related deaths and is reported to be resistant to chemotherapy caused by tumor-initiating cells. These tumor-initiating cells express stem cell markers. An accumulation of tumor-initiating cells can be found in 2% to 50% of all HCC and is correlated with a poor prognosis. Mechanisms that mediate chemoresistance include drug export, increased metabolism, and quiescence. Importantly, the mechanisms that regulate quiescence in tumor-initiating cells have not been analyzed in detail so far. In this research we have developed a single cell tracking method to follow up the fate of tumor-initiating cells during chemotherapy. Thereby, we were able to demonstrate that mCXCL1 exerts cellular state-specific effects regulating the resistance to chemotherapeutics. mCXCL1 is the mouse homolog of the human IL8, a chemokine that correlates with poor prognosis in HCC patients. We found that mCXCL1 blocks differentiation of premalignant cells and activates quiescence in tumor-initiating cells. This process depends on the activation of the mTORC1 kinase. Blocking of the mTORC1 kinase induces differentiation of tumor-initiating cells and allows their subsequent depletion using the chemotherapeutic drug doxorubicin. Our work deciphers the mCXCL1–mTORC1 pathway as crucial in liver cancer stem cell maintenance and highlights it as a novel target in combination with conventional chemotherapy. Cancer Res; 76(18); 5550–61. ©2016 AACR.
Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk
Authors: Patel Yesha M. , Park Sunghim L. , Han Younghun , Wilkens Lynne R. , Bickeböller Heike , Rosenberger Albert , Caporaso Neil , Landi Maria Teresa , Brüske Irene , Risch Angela , Wei Yongyue , Christiani David C. , Brennan Paul , Houlston Richard , McKay James , McLaughlin John , Hung Rayjean , Murphy Sharon , Stram Daniel O. , Amos Christopher , Le Marchand Loïc 
Published: August 2016

Abstract
Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3′-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P &lt; 5 × 10−8). CYP2A6 activity was correlated (r = 0.32; P &lt; 0.0001) with total nicotine equivalents (a measure of nicotine uptake). When we examined the effect of these variants on lung cancer risk in the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium GWAS dataset (13,479 cases and 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. Two hundred and twenty-six of the 248 variants associated with CYP2A6 activity in the MEC were available in TRICL. Of them, 81% had directionally consistent risk estimates, and six were globally significantly associated with lung cancer. When conditioning on nine known functional variants and two deletions, the top two SNPs (rs56113850 in MEC and rs35755165 in TRICL) remained significantly associated with CYP2A6 activity in MEC and lung cancer in TRICL. The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer. Although the variants identified in these studies may be used as risk prediction markers, the exact causal variants remain to be identified. Cancer Res; 76(19); 5768–76. ©2016 AACR.
TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy
Authors: Zhang Han , Chen Zheng , Miranda Roberto N. , Medeiros L. Jeffrey , McCarty Nami 
Published: August 2016

Abstract
Expression of the transglutaminase TG2 has been linked to constitutive activation of NF-κB and chemotherapy resistance in mantle cell lymphoma (MCL) cells. TG2 forms complexes with NF-κB components, but mechanistic insights that could be used to leverage therapeutic responses has been lacking. In the current study, we address this issue with the discovery of an unexpected role for TG2 in triggering autophagy in drug-resistant MCL cells through induction of IL6. CRISPR-mediated silencing of TG2 delayed apoptosis while overexpressing TG2 enhanced tumor progression. Under stress, TG2 and IL6 mediate enhanced autophagy formation to promote MCL cell survival. Interestingly, the autophagy product ATG5 involved in autophagosome elongation positively regulated TG2/NF-κB/IL6 signaling, suggesting a positive feedback loop. Our results uncover an interconnected network of TG2/NF-κB and IL6/STAT3 signaling with autophagy regulation in MCL cells, the disruption of which may offer a promising therapeutic strategy. Cancer Res; 76(21); 6410–23. ©2016 AACR.
The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma
Authors: Sandhu Vandana , Wedge David C. , Bowitz Lothe Inger Marie , Labori Knut Jørgen , Dentro Stefan C. , Buanes Trond , Skrede Martina L. , Dalsgaard Astrid M. , Munthe Else , Myklebost Ola , Lingjærde Ole Christian , Børresen-Dale Anne-Lise , Ikdahl Tone , Van Loo Peter , Nord Silje , Kure Elin H. 
Published: August 2016

AbstractDespite advances in diagnostics, less than 5% of patients with periampullary tumors experience an overall survival of five years or more. Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater, an enlargement of liver and pancreas ducts where they join and enter the small intestine. In this study, we analyzed copy number aberrations using Affymetrix SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo University Hospital to identify genome-wide copy number aberrations, putative driver genes, deregulated pathways, and potential prognostic markers. Results were validated in a separate cohort derived from The Cancer Genome Atlas Consortium (n = 127). In contrast to many other solid tumors, periampullary adenocarcinomas exhibited more frequent genomic deletions than gains. Genes in the frequently codeleted region 17p13 and 18q21/22 were associated with cell cycle, apoptosis, and p53 and Wnt signaling. By integrating genomics and transcriptomics data from the same patients, we identified CCNE1 and ERBB2 as candidate driver genes. Morphologic subtypes of periampullary adenocarcinomas (i.e., pancreatobiliary or intestinal) harbor many common genomic aberrations. However, gain of 13q and 3q, and deletions of 5q were found specific to the intestinal subtype. Our study also implicated the use of the PAM50 classifier in identifying a subgroup of patients with a high proliferation rate, which had impaired survival. Furthermore, gain of 18p11 (18p11.21-23, 18p11.31-32) and 19q13 (19q13.2, 19q13.31-32) and subsequent overexpression of the genes in these loci were associated with impaired survival. Our work identifies potential prognostic markers for periampullary tumors, the genetic characterization of which has lagged. Cancer Res; 76(17); 5092–102. ©2016 AACR.