bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Interface between Hepatitis B Virus Capsid Proteins Affects Self-Assembly, Pregenomic RNA Packaging, and Reverse Transcription
Authors: Tan Zhenning , Pionek Karolyn , Unchwaniwala Nuruddin , Maguire Megan L. , Loeb Daniel D. , Zlotnick Adam 
Published: January 2015

ABSTRACT

Hepatitis B virus (HBV) capsid proteins (Cps) assemble around the pregenomic RNA (pgRNA) and viral reverse transcriptase (P). pgRNA is then reverse transcribed to double-stranded DNA (dsDNA) within the capsid. The Cp assembly domain, which forms the shell of the capsid, regulates assembly kinetics and capsid stability. The Cp, via its nucleic acid-binding C-terminal domain, also affects nucleic acid organization. We hypothesize that the structure of the capsid may also have a direct effect on nucleic acid processing. Using structure-guided design, we made a series of mutations at the interface between Cp subunits that change capsid assembly kinetics and thermodynamics in a predictable manner. Assembly in cell culture mirrored
in vitro
activity. However, all of these mutations led to defects in pgRNA packaging. The amount of first-strand DNA synthesized was roughly proportional to the amount of RNA packaged. However, the synthesis of second-strand DNA, which requires two template switches, was not supported by any of the substitutions. These data demonstrate that the HBV capsid is far more than an inert container, as mutations in the assembly domain, distant from packaged nucleic acid, affect reverse transcription. We suggest that capsid molecular motion plays a role in regulating genome replication.

IMPORTANCE
The hepatitis B virus (HBV) capsid plays a central role in the virus life cycle and has been studied as a potential antiviral target. The capsid protein (Cp) packages the viral pregenomic RNA (pgRNA) and polymerase to form the HBV core. The role of the capsid in subsequent nucleic acid metabolism is unknown. Here, guided by the structure of the capsid with bound antiviral molecules, we designed Cp mutants that enhanced or attenuated the assembly of purified Cp
in vitro
. In cell culture, assembly of mutants was consistent with their
in vitro
biophysical properties. However, all of these mutations inhibited HBV replication. Specifically, changing the biophysical chemistry of Cp caused defects in pgRNA packaging and synthesis of the second strand of DNA. These results suggest that the HBV Cp assembly domain potentially regulates reverse transcription, extending the activities of the capsid protein beyond its presumed role as an inert compartment.
Contribution of MxB Oligomerization to HIV-1 Capsid Binding and Restriction
Authors: Buffone Cindy , Schulte Bianca , Opp Silvana , Diaz-Griffero Felipe 
Published: January 2015

ABSTRACT
The alpha interferon (IFN-α)-inducible restriction factor myxovirus B (MxB) blocks HIV-1 infection after reverse transcription but prior to integration. MxB binds to the HIV-1 core, which is composed of capsid protein, and this interaction leads to inhibition of the uncoating process of HIV-1. Previous studies suggested that HIV-1 restriction by MxB requires binding to capsid. This work tests the hypothesis that MxB oligomerization is important for the ability of MxB to bind to the HIV-1 core. For this purpose, we modeled the structure of MxB using the published tertiary structure of MxA. The modeled structure of MxB guided our mutagenic studies and led to the discovery of several MxB variants that lose the capacity to oligomerize. In agreement with our hypothesis, MxB variants that lost the oligomerization capacity also lost the ability to bind to the HIV-1 core. MxB variants deficient for oligomerization were not able to block HIV-1 infection. Overall, our work showed that oligomerization is required for the ability of MxB to bind to the HIV-1 core and block HIV-1 infection.

IMPORTANCE
MxB is a novel restriction factor that blocks infection of HIV-1. MxB is inducible by IFN-α, particularly in T cells. The current work studies the oligomerization determinants of MxB and carefully explores the contribution of oligomerization to capsid binding and restriction. This work takes advantage of the current structure of MxA and models the structure of MxB, which is used to guide structure-function studies. This work leads to the conclusion that MxB oligomerization is important for HIV-1 capsid binding and restriction.
A matched-group study protocol to evaluate the implementation of an Integrated Care Pathway programme for chronic obstructive pulmonary disease in Singapore
Authors: Wu Christine Xia , Tan Woan Shin , See Ryan Chor Kian , Yu Weichang , Kwek Lynette Siang Lim , Toh Matthias Paul Han Sim , Chee Thong Gan , Chua Gerald Seng Wee 
Published: January 2015

IntroductionThe treatment of chronic obstructive pulmonary disease (COPD) involves different care providers across care sites. This fragmentation of care increases the morbidity and mortality burden, as well as acute health services use. The COPD-Integrated Care Pathway (ICP) was designed and implemented to integrate the care across different sites from primary care to acute hospital and home. It aims to reduce the prevalence of COPD among the population in the catchment, reduce risk of hospital admissions, delay or prevent the progression of the disease and reduce mortality rate by adopting a coordinated and multidisciplinary approach to the management of the patients’ medical conditions. This study on the COPD-ICP programme is undertaken to determine the impact on processes of care, clinical outcomes and acute care utilisation.Methods and analysisThis will be a retrospective, pre-post, matched-groups study to evaluate the effectiveness of the COPD-ICP programme in improving clinical outcomes and reducing healthcare costs. Programme enrolees (intervention group) and non-enrolees (comparator group) will be matched using propensity scores. Administratively, we set 30% as our target for proportion admission difference between programme and non-programme patients. A sample size of 62 patients in each group will be needed for statistical comparisons to be made at 90% power. Adherence with recommended care elements will be measured at baseline and quarterly during 1-year follow-up. Risk of COPD-related hospitalisations as primary outcome, healthcare costs, disease progression and 1-year mortality during 1-year follow-up will be compared between the groups using generalised linear regression models.Ethics and disseminationThis protocol describes the implementation and proposed evaluation of the COPD-ICP programme. The described study has received ethical approval from the NHG Domain Specific Review Board (DSRB Ref: 2013/01200). Results of the study will be reported through peer-review publications and presentations at healthcare conferences.
Increased utilisation of primary healthcare in persons exposed to severe stress in prenatal life: a national population-based study in Denmark
Authors: Li Jiong , Yang Hu , Guldin Mai-Britt , Vedsted Peter , Vestergaard Mogens 
Published: January 2015

ObjectiveRecent studies have suggested that stress in a pregnant mother may affect the future health of the unborn child negatively. An excellent proxy for health problems is the use of healthcare resources. Using nationwide data, we examined whether persons born to mothers who lost a close relative during pregnancy have more contacts to general practice.DesignPopulation-based cohort study.SettingDenmark.ParticipantsWe included all children born in Denmark from 1973 to 2002 (N=2 032 528). Exposure of prenatal stress was defined as maternal bereavement by the death of a close relative during the antenatal period. The outcome of interest was contact with general practice between 2003 and 2009 when the participants were between 1 and 35 years of age. Poisson regression was used to assess the association between exposure and outcome.Outcome measuresContacts to general practitioner.ResultsOverall, persons exposed to prenatal stress had 2% more GP contacts than those not exposed, primarily due to increased utilisation of healthcare services during late adolescence and early adulthood. The exposed persons born to mothers who had lost a spouse had a higher risk (relative risk (RR) 1.12, 95% CI 1.10 to 1.14) and so did those born to mothers who had lost a close relative due to unexpected death (RR 1.06, 95% CI 1.05 to 1.06). Exposed persons had more contacts to general practice in daytime and more psychometric tests, talk therapies and C reactive protein tests than unexposed persons.ConclusionsPrenatal stress following maternal bereavement was associated with a slightly increased utilisation of primary healthcare, mainly due to increased healthcare needs related to mental health and infections. Understanding how stress during pregnancy influences the future health of the child is an important aspect of prenatal care.
An emerging evidence base for PET-CT in the management of childhood rhabdomyosarcoma: systematic review
Authors: Norman Gill , Fayter Debra , Lewis-Light Kate , Chisholm Julia , McHugh Kieran , Levine Daniel , Jenney Meriel , Mandeville Henry , Gatz Suzanne , Phillips Bob 
Published: January 2015

IntroductionRhabdomyosarcoma (RMS) management depends on risk stratification at diagnosis and treatment response. Assessment methods include CT, MRI, bone scintigraphy, histological analysis and bone marrow biopsy. Advanced functional imaging (FI) has potential to improve staging accuracy and management strategies.Methods and analysisWe conducted a systematic review (PROSPERO 2013:CRD42013006128) of diagnostic accuracy and clinical effectiveness of FI in histologically proven paediatric RMS. PRISMA guidance was followed. We searched 10 databases to November 2013. Studies with ≥10 patients with RMS which compared positron emission tomography (PET), PET-CT or diffusion-weighted imaging (DWI) MRI to conventional imaging at any treatment stage were included. Study quality was assessed. Limited, heterogeneous effectiveness data required narrative synthesis, illustrated by plotting sensitivity and specificity in receiver operating curve (ROC) space.ResultsEight studies (six PET-CT, two PET) with 272 RMS patients in total were included. No DWI-MRI studies met inclusion criteria. Pooled estimates were not calculated due to sparseness of data. Limited evidence indicated initial PET-CT results were predictive of survival. PET-CT changed management of 7/40 patients. Nodal involvement PET-CT: sensitivity ranged from 80% to 100%; specificity from 89% to 100%. Distant metastatic involvement: PET-CT sensitivity ranged from 95% to 100%; specificity from 80% to100%. Data on metastases in different sites were sparse. Limited data were found on outcome prediction by PET-CT response.Dissemination and ethicsPET/PET-CT may increase initial staging accuracy in paediatric RMS, specifically in the detection of nodal involvement and distant metastatic spread. There is a need to further assess PET-CT for this population, ideally in a representative, unbiased and transparently selected cohort of patients.
Treatment approaches of palliative medicine specialists for depression in the palliative care setting: findings from a qualitative, in-depth interview study
Authors: Ng Felicity , Crawford Gregory B , Chur-Hansen Anna 
Published: January 2015

BackgroundTreatment of depression in the palliative care setting is complicated by varied treatment preferences, a small body of research, and unique challenges associated with the end-of-life. Little is known about the treatment practices of medical practitioners in this setting.ObjectiveThis study aimed to investigate and characterise the treatment approaches of palliative medicine specialists for depression.DesignSemistructured, in-depth interviews were conducted to explore explanatory models of depression from palliative medicine specialists, including a focus on treatment. Verbatim interview transcripts were analysed for themes.Setting/participantsPalliative medicine specialists practising in Australia were recruited and purposively sampled. Nine participants were interviewed to reach data saturation.ResultsFive themes were identified in relation to treatment of depression: (1) guiding principles of treatment; (2) treatment approaches; (3) factors underpinning treatment decisions; (4) difficulties arising in treatment; and (5) interdisciplinary roles. Participants described five distinct treatment approaches, consisting of biological orientation, psychosocial orientation, combination approach, undifferentiated approach and ambivalence. Treatment decisions were contingent on patient, depression, clinician and sociocultural factors. Difficulties included discomfort with treating depression, being inadequately equipped and confronting therapeutic limitations. Treating depression was considered to require multidisciplinary team effort.ConclusionsPalliative medicine specialists’ treatment approaches are linked to their concepts of and causal explanations for depression. Future treatment guidelines could aim to consider specific varieties of depression, be more differentiated in treatment modality and type, and consider decision-shaping factors. Continuing mental health education and the incorporation of psychiatry and psychology into palliative care services may have enduring benefits.
Effect of signs of oestrus, disease stressors and cow activity on pregnancy rate following artificial insemination
Authors: Bijker I. , Christley R. M. , Smith R. F. , Dobson H. 
Published: January 2015

The objective was to examine (a) how pregnancy rate on one farm (500 cows) was affected by signs of oestrus and disease stressors and (b) whether pregnancy rate could be maximised by considering cow activity. The signs of oestrus and timings were recorded at artificial insemination (AI), and cow activity was monitored by neck collars. Pregnancy rate tended to be higher in animals that displayed standing oestrus (35 v 26 per cent; P=0.06) but was 10 per cent lower in those cows with an elevated somatic cell count (SCC; >200,000 cells/ml milk) within 0–4 or 4–8 weeks prior to AI (P=0.01 and 0.05, respectively), irrespective of the incidence of clinical mastitis prior to AI. Cow activity data were available for 525 inseminations (from a total of 1299). The mean interval from increased activity to AI in all cows (11 hours 32 minutes; 95 per cent CI 10 hours 40 minutes to 12 hours 24 minutes) was not different for cows that did or did not establish a pregnancy (P=0.90). The pregnancy rate improved to the average of unaffected cows if AI was delayed by about eight hours in animals with an elevated SCC 0–4 weeks prior to AI (P=0.025), indicating that, in cows with prior elevated SCC, AI could be repeated approximately eight hours later to achieve maximum pregnancy rates.
Mechanical stability of engineered barriers in a subsurface disposal facility during gas migration based on coupled hydromechanical modelling
Authors: Yamamoto Shuichi , Kumagai Mamoru , Koga Kazumasa , Sato Shin 
Published: January 2015

Abstract
The ‘subsurface disposal’ concept has been proposed for relatively higher-activity low-level waste (LLW) in Japan. This concept includes a low-permeability layer (LPL) made of bentonite material and a low-diffusion layer (LDL) made of dense cementitious material. The influence of gas generation and migration on the mechanical stability of the engineered barrier system (EBS) is one of the issues for long-term performance assessment of the disposal facility. In this study, coupled hydromechanical modelling and analyses are carried out in order to evaluate the mechanical stability of the system. Two gas generation rate cases are simulated: (1) a reference case; and (2) a conservative case. It is found from the analyses that the tensile stress developed in the cementitious components due to accumulated gas pressure is lower than the tensile strength of the materials, and that stress developed in the LPL remains compressive apart from at the interface between the LPL and the LDL, which suggests that opening could occur at the interface. These results indicate that the gas pressure would not mechanically damage the EBS of the subsurface disposal even if a relatively high gas generation rate were assumed.
Electronic Nicotine Delivery Systems: A Policy Statement from the American Association for Cancer Research and the American Society of Clinical Oncology
Authors: Brandon Thomas H. , Goniewicz Maciej L. , Hanna Nasser H. , Hatsukami Dorothy K. , Herbst Roy S. , Hobin Jennifer A. , Ostroff Jamie S. , Shields Peter G. , Toll Benjamin A. , Tyne Courtney A. , Viswanath Kasisomayajula , Warren Graham W. 
Published: January 2015

Abstract
Combustible tobacco use remains the number one preventable cause of disease, disability, and death in the United States. Electronic nicotine delivery systems (ENDS), which include e-cigarettes, are devices capable of delivering nicotine in an aerosolized form. ENDS use by both adults and youth has increased rapidly, and some have advocated these products could serve as harm-reduction devices and smoking cessation aids. ENDS may be beneficial if they reduce smoking rates or prevent or reduce the known adverse health effects of smoking. However, ENDS may also be harmful, particularly to youth, if they increase the likelihood that nonsmokers or formers smokers will use combustible tobacco products or if they discourage smokers from quitting. The American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) recognize the potential ENDS have to alter patterns of tobacco use and affect the public's health; however, definitive data are lacking. AACR and ASCO recommend additional research on these devices, including assessing the health impacts of ENDS, understanding patterns of ENDS use, and determining what role ENDS have in cessation. Key policy recommendations include supporting federal, state, and local regulation of ENDS; requiring manufacturers to register with the FDA and report all product ingredients, requiring childproof caps on ENDS liquids, and including warning labels on products and their advertisements; prohibiting youth-oriented marketing and sales; prohibiting child-friendly ENDS flavors; and prohibiting ENDS use in places where cigarette smoking is prohibited. Clin Cancer Res; 21(3); 514–25. ©2015 AACR. American Association for Cancer Research and American Society of Clinical Oncology.
Zebrafish: A New Companion for Translational Research in Oncology
Authors: Barriuso Jorge , Nagaraju Raghavendar , Hurlstone Adam 
Published: January 2015

Abstract
In an era of high-throughput “omic” technologies, the unprecedented amount of data that can be generated presents a significant opportunity but simultaneously an even greater challenge for oncologists trying to provide personalized treatment. Classically, preclinical testing of new targets and identification of active compounds against those targets have entailed the extensive use of established human cell lines, as well as genetically modified mouse tumor models. Patient-derived xenografts in zebrafish may in the near future provide a platform for selecting an appropriate personalized therapy and together with zebrafish transgenic tumor models represent an alternative vehicle for drug development. The zebrafish is readily genetically modified. The transparency of zebrafish embryos and the recent development of pigment-deficient zebrafish afford researchers the valuable capacity to observe directly cancer formation and progression in a live vertebrate host. The zebrafish is amenable to transplantation assays that test the serial passage of fluorescently labeled tumor cells as well as their capacity to disseminate and/or metastasize. Progress achieved to date in genetic engineering and xenotransplantation will establish the zebrafish as one of the most versatile animal models for cancer research. A model organism that can be used in transgenesis, transplantation assays, single-cell functional assays, and in vivo imaging studies make zebrafish a natural companion for mice in translational oncology research. Clin Cancer Res; 21(5); 969–75. ©2015 AACR.
The MDM2 Inhibitor AMG 232 Demonstrates Robust Antitumor Efficacy and Potentiates the Activity of p53-Inducing Cytotoxic Agents
Authors: Canon Jude , Osgood Tao , Olson Steven H. , Saiki Anne Y. , Robertson Rebecca , Yu Dongyin , Eksterowicz John , Ye Qiuping , Jin Lixia , Chen Ada , Zhou Jing , Cordover David , Kaufman Stephen , Kendall Richard , Oliner Jonathan D. , Coxon Angela , Radinsky Robert 
Published: January 2015

Abstract
p53 is a critical tumor suppressor and is the most frequently inactivated gene in human cancer. Inhibition of the interaction of p53 with its negative regulator MDM2 represents a promising clinical strategy to treat p53 wild-type tumors. AMG 232 is a potential best-in-class inhibitor of the MDM2–p53 interaction and is currently in clinical trials. We characterized the activity of AMG 232 and its effect on p53 signaling in several preclinical tumor models. AMG 232 binds the MDM2 protein with picomolar affinity and robustly induces p53 activity, leading to cell-cycle arrest and inhibition of tumor cell proliferation. AMG 232 treatment inhibited the in vivo growth of several tumor xenografts and led to complete and durable regression of MDM2-amplified SJSA-1 tumors via growth arrest and induction of apoptosis. Therapeutic combination studies of AMG 232 with chemotherapies that induce DNA damage and p53 activity resulted in significantly superior antitumor efficacy and regression, and markedly increased activation of p53 signaling in tumors. These preclinical data support the further evaluation of AMG 232 in clinical trials as both a monotherapy and in combination with standard-of-care cytotoxics. Mol Cancer Ther; 14(3); 649–58. ©2015 AACR.
Systematic siRNA Screen Unmasks NSCLC Growth Dependence by Palmitoyltransferase DHHC5
Authors: Tian Hui , Lu Jui-Yun , Shao Chunli , Huffman Kenneth E. , Carstens Ryan M. , Larsen Jill E. , Girard Luc , Liu Hui , Rodriguez-Canales Jaime , Frenkel Eugene P. , Wistuba Ignacio I. , Minna John D. , Hofmann Sandra L. 
Published: January 2015

Abstract
Protein S-palmitoylation is a widespread and dynamic posttranslational modification that regulates protein–membrane interactions, protein–protein interactions, and protein stability. A large family of palmitoyl acyl transferases, termed the DHHC family due to the presence of a common catalytic motif, catalyzes S-palmitoylation; the role of these enzymes in cancer is largely unexplored. In this study, an RNAi-based screen targeting all 23 members of the DHHC family was conducted to examine the effects on the growth in non–small cell lung cancer (NSCLC). Interestingly, siRNAs directed against DHHC5 broadly inhibited the growth of multiple NSCLC lines but not normal human bronchial epithelial cell (HBEC) lines. Silencing of DHHC5 by lentivirus-mediated expression of DHHC5 shRNAs dramatically reduced in vitro cell proliferation, colony formation, and cell invasion in a subset of cell lines that were examined in further detail. The phenotypes were restored by transfection of a wild-type DHHC5 plasmid but not by a plasmid expressing a catalytically inactive DHHC5. Tumor xenograft formation was severely inhibited by DHHC5 knockdown and rescued by DHHC5 expression, using both a conventional and tetracycline-inducible shRNA. These data indicate that DHHC5 has oncogenic capacity and contributes to tumor formation in NSCLC, thus representing a potential novel therapeutic target.
Implications: Inhibitors of DHHC5 enzyme activity may inhibit non–small cell lung cancer growth. Mol Cancer Res; 13(4); 784–94. ©2015 AACR.