bluuebunny/crossref_metadata_2025_split huggingface dataset:
Asymmetric Modification of Hepatitis B Virus (HBV) Genomes by an Endogenous Cytidine Deaminase inside HBV Cores Informs a Model of Reverse Transcription
Authors: Nair Smita , Zlotnick Adam 
Published: February 2018

ABSTRACT
Cytidine deaminases inhibit replication of a broad range of DNA viruses by deaminating cytidines on single-stranded DNA (ssDNA) to generate uracil. While several lines of evidence have revealed hepatitis B virus (HBV) genome editing by deamination, it is still unclear which nucleic acid intermediate of HBV is modified. Hepatitis B virus has a relaxed circular double-stranded DNA (rcDNA) genome that is reverse transcribed within virus cores from a RNA template. The HBV genome also persists as covalently closed circular DNA (cccDNA) in the nucleus of an infected cell. In the present study, we found that in HBV-producing HepAD38 and HepG2.2.15 cell lines, endogenous cytidine deaminases edited 10 to 25% of HBV rcDNA genomes, asymmetrically with almost all mutations on the 5′ half of the minus strand. This region corresponds to the last half of the minus strand to be protected by plus-strand synthesis. Within this half of the genome, the number of mutations peaks in the middle. Overexpressed APOBEC3A and APOBEC3G could be packaged in HBV capsids but did not change the amount or distribution of mutations. We found no deamination on pregenomic RNA (pgRNA), indicating that an intact genome is encapsidated and deaminated during or after reverse transcription. The deamination pattern suggests a model of rcDNA synthesis in which pgRNA and then newly synthesized minus-sense single-stranded DNA are protected from deaminase by interaction with the virus capsid; during plus-strand synthesis, when enough dsDNA has been synthesized to displace the remaining minus strand from the capsid surface, the single-stranded DNA becomes deaminase sensitive.

IMPORTANCE
Host-induced mutation of the HBV genome by APOBEC proteins may be a path to clearing the virus. We examined cytidine-to-thymidine mutations in the genomes of HBV particles grown in the presence or absence of overexpressed APOBEC proteins. We found that genomes were subjected to deamination activity during reverse transcription, which takes place within the virus capsid. These observations provide a direct insight into the mechanics of reverse transcription, suggesting that newly synthesized dsDNA displaces ssDNA from the capsid walls, making the ssDNA accessible to deaminase activity.
Can doctors and patients correctly estimate cardiovascular risk? A cross-sectional study in primary care
Authors: Liew Su May , Lee Wai Khew , Khoo Ee Ming , Ismail Irmi Zarina , Ambigapathy Subashini , Omar Mimi , Suleiman Siti Zaleha , Saaban Juwita , Mohd Zaidi Nur Farhana , Yusoff Harmy 
Published: February 2018

ObjectiveAccurate cardiovascular risk estimations by patients and doctors are important as these affect health behaviour and medical decision making. We aimed to determine if doctors and patients were accurately estimating the absolute cardiovascular risk of patients in primary care.MethodsA cross-sectional study was carried out in primary care clinics in Malaysia in 2014. Patients aged 35 years and above without known cardiovascular disease (CVDs) were included. Face-to-face interviews with a structured questionnaire were used to collect sociodemographic and clinical data as well as patients’ perception and doctors’ estimate of the patients’ CVD risk. Associations were tested using χ2, correlation and independent t-tests.ResultsWe recruited 1094 patients and 57 doctors. Using the Framingham Risk Score (FRS) alone, 508 patients (46.4%) were in the high-risk group. When diabetes was included as high risk, the number increased to 776 (70.9%). Only 34.4% of patients and 55.7% of doctors correctly estimated the patient’s CVD risk in comparison with the reference FRS.Of the high-risk patients, 664 (85.6%) underestimated their CV risk. Factors associated with underestimation by patients included not having family history of CVD (adjusted OR (AOR): 2.705, 95% CI 1.538 to 4.757), smaller waist circumference (AOR: 0.979,95% CI 0.960 to 0.999) and ethnicity in comparison with the Malay as reference group (indigenous/others: AOR: 0.129, 95% CI 0.071 to 0.235). Doctors underestimated risk in 59.8% of the high-risk group. Factors associated with underestimation by doctors were patients factors such as being female (AOR: 2.232, 95% CI 1.460 to 3.410), younger age (AOR: 0.908, 95% CI 0.886 to 0.930), non-hypertensive (AOR: 1.731, 95% CI 1.067 to 2.808), non-diabetic (AOR: 1.931, 95% CI 1.114 to 3.348), higher high-density lipoprotein levels (AOR: 3.546, 95% CI 2.025 to 6.209), lower systolic blood pressure (AOR: 0.970, 95% CI 0.957 to 0.982), non-smoker (AOR: 2.246, 95% CI 1.354 to 3.726) and ethnicity in comparison with the Malay as reference group (Indian: AOR: 0.430, 95% CI 0.257 to 0.720; indigenous/others: AOR: 2.498, 95% CI 1.346 to 4.636).ConclusionsThe majority of consultations occurring between doctors and patients are being informed by inaccurate cardiovascular risk estimation.
Electroacupuncture for poststroke spasticity (EAPSS): protocol for a randomised controlled trial
Authors: Cai Yiyi , Zhang Claire Shuiqing , Ouyang Wenwei , Li Jianmin , Nong Wenheng , Zhang Anthony Lin , Xue Charlie Changli , Wen Zehuai 
Published: February 2018

IntroductionSpasticity is a common complication of stroke. Current therapies for poststroke spasticity (PSS) have been reported to be associated with high costs, lack of long-term benefit and unwanted adverse events (AEs). Electroacupuncture (EA) has been used for PSS, however, its efficacy and safety is yet to be confirmed by high-quality clinical studies. This study is designed to evaluate the add-on effects and safety profile of EA when used in combination with usual care (UC).Methods and analysisThis study is a parallel group randomised controlled trial. A total of 136 participants will be included and randomly assigned to either the treatment group (EA plus UC) or the control group (UC alone). Prior to the main trial, a pilot study involving 30 participants will be conducted to assess the feasibility of the trial protocol. EA will be administered by registered acupuncturists for 20min to 30 min, three times per week for 4 weeks. The primary outcome measure (Modified Ashworth Scale) and secondary outcome measures (Fugl-Meyer Assessment and Barthel Index) will be evaluated at baseline, the end of treatment (week 4) and the end of follow-up (week 8). AEs will be monitored, recorded and reported, and their causality will be explored.Ethics and disseminationEthics approval was obtained from the ethics committees of Guangdong Provincial Hospital of Chinese Medicine and RMIT University in December 2016. The results will be disseminated in a peer-reviewed journal, and PhD theses and might be presented at international conferences.Trial registration numberChiCTR-IOR-16010283; Pre-results.
Reliability of wireless monitoring using a wearable patch sensor in high-risk surgical patients at a step-down unit in the Netherlands: a clinical validation study
Authors: Breteler Martine J M , Huizinga Erik , van Loon Kim , Leenen Luke P H , Dohmen Daan A J , Kalkman Cor J , Blokhuis Taco J 
Published: February 2018

Background and objectivesIntermittent vital signs measurements are the current standard on hospital wards, typically recorded once every 8 hours. Early signs of deterioration may therefore be missed. Recent innovations have resulted in ‘wearable’ sensors, which may capture patient deterioration at an earlier stage. The objective of this study was to determine whether a wireless ‘patch’ sensor is able to reliably measure respiratory and heart rate continuously in high-risk surgical patients. The secondary objective was to explore the potential of the wireless sensor to serve as a safety monitor.DesignIn an observational methods comparisons study, patients were measured with both the wireless sensor and bedside routine standard for at least 24 hours.SettingUniversity teaching hospital, single centre.ParticipantsTwenty-five postoperative surgical patients admitted to a step-down unit.Outcome measuresPrimary outcome measures were limits of agreement and bias of heart rate and respiratory rate. Secondary outcome measures were sensor reliability, defined as time until first occurrence of data loss.Results1568 hours of vital signs data were analysed. Bias and 95% limits of agreement for heart rate were −1.1 (−8.8 to 6.5) beats per minute. For respiration rate, bias was −2.3 breaths per minute with wide limits of agreement (−15.8 to 11.2 breaths per minute). Median filtering over a 15 min period improved limits of agreement of both respiration and heart rate. 63% of the measurements were performed without data loss greater than 2 min. Overall data loss was limited (6% of time).ConclusionsThe wireless sensor is capable of accurately measuring heart rate, but accuracy for respiratory rate was outside acceptable limits. Remote monitoring has the potential to contribute to early recognition of physiological decline in high-risk patients. Future studies should focus on the ability to detect patient deterioration on low care environments and at home after discharge.
Predictors of symptomatic intracranial haemorrhage in patients with an ischaemic stroke with neurological deterioration after intravenous thrombolysis
Authors: James Brandon , Chang Andrew D , McTaggart Ryan A , Hemendinger Morgan , Mac Grory Brian , Cutting Shawna M , Burton Tina M , Reznik Michael E , Thompson Bradford , Wendell Linda , Mahta Ali , Siket Matthew , Madsen Tracy E , Sheth Kevin N , Nouh Amre , Furie Karen L , Jayaraman Mahesh V , Khatri Pooja , Yaghi Shadi 
Published: February 2018

ObjectivesEarly neurological deterioration prompting urgent brain imaging occurs in nearly 15% of patients with ischaemic stroke receiving intravenous tissue plasminogen activator (tPA). We aim to determine risk factors associated with symptomatic intracranial haemorrhage (sICH) in patients with ischaemic stroke undergoing emergent brain imaging for early neurological deterioration after receiving tPA.MethodsWe abstracted data from our prospective stroke database and included all patients receiving tPA for ischaemic stroke between 1 March 2015 and 1 March 2017. We then identified patients with neurological deterioration who underwent urgent brain imaging prior to their per-protocol surveillance imaging and divided patients into two groups: those with and without sICH. We compared baseline demographics, clinical variables, in-hospital treatments and functional outcomes at 90 days between the two groups.ResultsWe identified 511 patients who received tPA, of whom 108 (21.1%) had an emergent brain CT. Of these patients, 17.5% (19/108) had sICH; 21.3% (23/108) of emergent scans occurred while tPA was infusing, though only 4.3% of these scans (1/23) revealed sICH. On multivariable analyses, the only predictor of sICH was a change in level of consciousness (OR 6.62, 95% CI 1.64 to 26.70, P=0.008).ConclusionChange in level of consciousness is associated with sICH among patients undergoing emergent brain imaging after receiving tPA. In this group of patients, preparation of tPA reversal agents while awaiting brain imaging may reduce reversal times. Future studies are needed to study the cost-effectiveness of this approach.
Association ofinterleukin-10gene single nucleotide polymorphisms with rheumatoid arthritis in a Chinese population
Authors: Zhang Tian-Ping , Lv Tian-Tian , Xu Shu-Zhen , Pan Hai-Feng , Ye Dong-Qing 
Published: February 2018

AbstractPurpose of the studyIncreasing numbers of studies show that interleukin (IL)-10 plays a key role in the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and acts as an immunomodulatory cytokine. The purpose of the present study was to analyse the relationship between gene single nucleotide polymorphisms (SNPs) in the IL-10 gene and RA susceptibility.Study designWe genotyped three SNPs (rs1800890, rs3024495, rs3024505) of the IL-10 gene in a Chinese population of 354 RA patients and 367 controls. Genotyping was conducted using TaqMan SNP genotyping assays. Plasma IL-10 levels were measured by ELISA.ResultsThe A allele of the rs1800890 variant was significantly related to decreased risk for RA compared with the T allele (A vs T: OR 0.580, 95% CI 0.345 to 0.975, P=0.038). No significant association between the genotype distribution of these SNPs and RA susceptibility was detected. The genotype effect of the dominant model was also evaluated, but no statistical difference was found. Further analysis in RA patients demonstrated that none of these SNPs were associated with rheumatoid factor (RF) or anti-citrullinated protein antibody (anti-CCP). In addition, no significant differences in plasma IL-10 levels were observed among RA patients with different genotypes.ConclusionsThe IL-10 rs1800890 variant might contribute to RA susceptibility in the Chinese population. Replication studies in different ethnic groups are required to further examine the critical role of IL-10 gene variation in the pathogenesis of RA.
Maximising the value of Portable XRF data in exploration: An example from Marirongoe, Mozambique
Authors: Sterk René , Gazley Michael F. , Wood Matthew P. , Collins Katie S. , Collis Geoff 
Published: February 2018

Here we present a portable X-ray fluorescence (pXRF) dataset collected
in situ
(
n
= 1591) and a laboratory dataset (
n

=
226) from a soil sampling campaign in Marirongoe, Mozambique, to document the strength of rapid geochemical data collection in the field during mineral exploration. Real-time mapping of the geochemistry of underlying granite by utilising pXRF analysis of soil samples identified variation in granitic composition, thus allowing exploration to rapidly focus on the most prospective areas for Ta-Nb-U-REE mineralization. Principal components analysis and clustering protocols are applied to the centred log-ratio transform of a selection of eight elements (Ca, Fe, K, Rb, Sr, Ti, Mn, and Zr) to identify rocks of the same geochemical affinity
a posteriori.
Maps of these clusters reveal a map pattern that provides an interpretation of the underlying geology. One of the limitations of pXRF is false elemental concentrations being detected due to spectral overlaps between elements. We provide a possible solution to this problem through statistical data analysis using a probabilistic modelling approach. We propose a binary approach whereby the pXRF data for these elements, such as Sn, can be considered in the context of presence (detected; >150 ppm) or absence (not detected; <150 ppm) as comparison to laboratory data shows that the concentration of Sn is reliably detected at concentrations >150 ppm. A kernel density estimator and Bayes conditional probability can provide an effective method for calculating the probability of a sample having elevated content of elements, such as Sn, which may be variably detected by pXRF (depending on matrix and concentration). Utilising statistical approaches to treat large geochemical datasets, such as those that can be generated by pXRF, as they are collected, can provide timely and significant insights that might otherwise not have been apparent in elemental concentration maps alone.
CO
2
sublimation in Martian gullies: laboratory experiments at varied slope angle and regolith grain sizes
Authors: Sylvest Matthew E. , Dixon John C. , Conway Susan J. , Patel Manish R. , McElwaine Jim N. , Hagermann Axel , Barnes Adam 
Published: February 2018

Abstract

Martian gullies were initially hypothesized to be carved by liquid water, due to their resemblance to gullies on Earth. Recent observations have highlighted significant sediment transport events occurring in Martian gullies at times and places where CO
2
ice should be actively sublimating. Here we explore the role of CO
2
sublimation in mobilizing sediment through laboratory simulation. In our previous experimental work, we reported the first observations of sediment slope movement triggered by the sublimation of CO
2
frost. We used a Mars regolith simulant near the angle of repose. The current study extends our previous work by including two additional substrates, fine and coarse sand, and by testing slope angles down to 10°. We find that the Mars regolith simulant is active down to 17°, the fine sand is active only near the angle of repose and the coarse sand shows negligible movement. Using an analytical model, we show that under Martian gravity motion should be possible at even lower slope angles. We conclude that these mass-wasting processes could be involved in shaping Martian gullies at the present day and intriguingly the newly reported CO
2
-creep process could provide an alternative explanation for putative solifluction lobes on Mars.
A Tricin Derivative from Deschampsia antarctica Desv. Inhibits Colorectal Carcinoma Growth and Liver Metastasis through the Induction of a Specific Immune Response
Authors: Malvicini Mariana , Gutierrez-Moraga Ana , Rodriguez Marcelo M. , Gomez-Bustillo Sofia , Salazar Lorena , Sunkel Carlos , Nozal Leonor , Salgado Antonio , Hidalgo Manuel , Lopez-Casas Pedro P. , Novella Jose Luis , Vaquero Juan Jose , Alvarez-Builla Julio , Mora Adda , Gidekel Manuel , Mazzolini Guillermo 
Published: February 2018

Abstract
In colorectal carcinoma patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic colorectal carcinoma have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina is an antitumor agent isolated from Deschampsia antarctica Desv. This study aimed to evaluate the antitumor properties of Antartina in colorectal carcinoma models. We used human and murine colorectal carcinoma cell lines for investigating proliferation, apoptosis, and cell-cycle effects of Antartina therapy in vitro. Avatar and immunocompetent colorectal carcinoma animal models were applied for evaluating the effects of Antartina in vivo. Immune response against colorectal carcinoma model was investigated using CTL assay, analyzing dendritic cell activation and intratumor T-cell subpopulation, and by tumor rechallenge experiments. Antartina inhibits in vitro human colorectal carcinoma cell proliferation; however, in vivo experiments in Avatar colorectal carcinoma model Antartina display a limited antitumor effect. In an immunocompetent colorectal carcinoma mice model, Antartina potently inhibited tumor growth and liver metastases, leading to complete tumor regressions in &gt;30% of mice and increased animal survival. In addition, Antartina induced a potent specific cytotoxic T-cell response against colorectal carcinoma and a long-lasting antitumor immunity. Interestingly, Antartina increased tumor immunogenicity and stimulated dendritic cell activation. No toxic effects were observed at the doses employed. Our findings showed that Antartina has the ability to induce antitumor immunity against colorectal carcinoma and can be used to develop new tools for the treatment of colorectal carcinoma. Mol Cancer Ther; 17(5); 966–76. ©2018 AACR.
Combined Inhibition of mTOR and CDK4/6 Is Required for Optimal Blockade of E2F Function and Long-term Growth Inhibition in Estrogen Receptor–positive Breast Cancer
Authors: Michaloglou Chrysiis , Crafter Claire , Siersbaek Rasmus , Delpuech Oona , Curwen Jon O. , Carnevalli Larissa S. , Staniszewska Anna D. , Polanska Urszula M. , Cheraghchi-Bashi Azadeh , Lawson Mandy , Chernukhin Igor , McEwen Robert , Carroll Jason S. , Cosulich Sabina C. 
Published: February 2018

Abstract
The cyclin dependent kinase (CDK)–retinoblastoma (RB)–E2F pathway plays a critical role in the control of cell cycle in estrogen receptor–positive (ER+) breast cancer. Small-molecule inhibitors of CDK4/6 have shown promise in this tumor type in combination with hormonal therapies, reflecting the particular dependence of this subtype of cancer on cyclin D1 and E2F transcription factors. mTOR inhibitors have also shown potential in clinical trials in this disease setting. Recent data have suggested cooperation between the PI3K/mTOR pathway and CDK4/6 inhibition in preventing early adaptation and eliciting growth arrest, but the mechanisms of the interplay between these pathways have not been fully elucidated. Here we show that profound and durable inhibition of ER+ breast cancer growth is likely to require multiple hits on E2F-mediated transcription. We demonstrate that inhibition of mTORC1/2 does not affect ER function directly, but does cause a decrease in cyclin D1 protein, RB phosphorylation, and E2F-mediated transcription. Combination of an mTORC1/2 inhibitor with a CDK4/6 inhibitor results in more profound effects on E2F-dependent transcription, which translates into more durable growth arrest and a delay in the onset of resistance. Combined inhibition of mTORC1/2, CDK4/6, and ER delivers even more profound and durable regressions in breast cancer cell lines and xenografts. Furthermore, we show that CDK4/6 inhibitor–resistant cell lines reactivate the CDK–RB–E2F pathway, but remain sensitive to mTORC1/2 inhibition, suggesting that mTORC1/2 inhibitors may represent an option for patients that have relapsed on CDK4/6 therapy. Mol Cancer Ther; 17(5); 908–20. ©2018 AACR.
Characterization of ABBV-221, a Tumor-Selective EGFR-Targeting Antibody Drug Conjugate
Authors: Phillips Andrew C. , Boghaert Erwin R. , Vaidya Kedar S. , Falls Hugh D. , Mitten Michael J. , DeVries Peter J. , Benatuil Lorenzo , Hsieh Chung-Ming , Meulbroek Jonathan A. , Panchal Sanjay C. , Buchanan Fritz G. , Durbin Kenneth R. , Voorbach Martin J. , Reuter David R. , Mudd Sarah R. , Loberg Lise I. , Ralston Sherry L. , Cao Diana , Gan Hui K. , Scott Andrew M. , Reilly Edward B. 
Published: February 2018

AbstractDepatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR, highlighting the need for therapies with activity against tumors with nonamplified EGFR overexpression. In addition, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR-targeting ADC comprised of an affinity-matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR-positive tumor cells and greater in vitro potency. ABBV-221 displays increased tumor uptake and antitumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR-amplified GBM patient derived xenograft (PDX) model and is highly effective alone and in combination with standard-of-care temozolomide in an EGFRvIII-positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase I clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR. Mol Cancer Ther; 17(4); 795–805. ©2018 AACR.