bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly
Authors: Wu Shuo , Zhao Qiong , Zhang Pinghu , Kulp John , Hu Lydia , Hwang Nicky , Zhang Jiming , Block Timothy M. , Xu Xiaodong , Du Yanming , Chang Jinhong , Guo Ju-Tao 
Published: June 2017

ABSTRACT
Chronic hepatitis B virus (HBV) infection is a global public health problem. Although the currently approved medications can reliably reduce the viral load and prevent the progression of liver diseases, they fail to cure the viral infection. In an effort toward discovery of novel antiviral agents against HBV, a group of benzamide (BA) derivatives that significantly reduced the amount of cytoplasmic HBV DNA were discovered. The initial lead optimization efforts identified two BA derivatives with improved antiviral activity for further mechanistic studies. Interestingly, similar to our previously reported sulfamoylbenzamides (SBAs), the BAs promote the formation of empty capsids through specific interaction with HBV core protein but not other viral and host cellular components. Genetic evidence suggested that both SBAs and BAs inhibited HBV nucleocapsid assembly by binding to the heteroaryldihydropyrimidine (HAP) pocket between core protein dimer-dimer interfaces. However, unlike SBAs, BA compounds uniquely induced the formation of empty capsids that migrated more slowly in native agarose gel electrophoresis from A36V mutant than from the wild-type core protein. Moreover, we showed that the assembly of chimeric capsids from wild-type and drug-resistant core proteins was susceptible to multiple capsid assembly modulators. Hence, HBV core protein is a dominant antiviral target that may suppress the selection of drug-resistant viruses during core protein-targeting antiviral therapy. Our studies thus indicate that BAs are a chemically and mechanistically unique type of HBV capsid assembly modulators and warranted for further development as antiviral agents against HBV.

IMPORTANCE
HBV core protein plays essential roles in many steps of the viral replication cycle. In addition to packaging viral pregenomic RNA (pgRNA) and DNA polymerase complex into nucleocapsids for reverse transcriptional DNA replication to take place, the core protein dimers, existing in several different quaternary structures in infected hepatocytes, participate in and regulate HBV virion assembly, capsid uncoating, and covalently closed circular DNA (cccDNA) formation. It is anticipated that small molecular core protein assembly modulators may disrupt one or multiple steps of HBV replication, depending on their interaction with the distinct quaternary structures of core protein. The discovery of novel core protein-targeting antivirals, such as benzamide derivatives reported here, and investigation of their antiviral mechanism may lead to the identification of antiviral therapeutics for the cure of chronic hepatitis B.
Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation
Authors: Kosowicz John G. , Lee Jaeyeun , Peiffer Brandon , Guo Zufeng , Chen Jianmeng , Liao Gangling , Hayward S. Diane , Liu Jun O. , Ambinder Richard F. 
Published: June 2017

ABSTRACT
Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block B cell receptor (BCR) signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction. Further investigation shows that mammalian target of rapamycin complex 2 (mTORC2) contributes to BCR-mediated lytic induction and that FK506-binding protein 12 (FKBP12) binding alone is not adequate to block activation. Finally, we show that BCR signaling can activate EBV lytic induction in freshly isolated B cells from peripheral blood mononuclear cells (PBMCs) and that activation can be inhibited by ibrutinib or idelalisib.

IMPORTANCE
EBV establishes viral latency in B cells. Activation of the B cell receptor pathway activates lytic viral expression in cell lines. Here we show that drugs that inhibit important kinases in the BCR signaling pathway inhibit activation of lytic viral expression but do not inhibit several other lytic activation pathways. Immunosuppressant drugs such as cyclosporine and tacrolimus but not rapamycin also inhibit BCR-mediated EBV activation. Finally, we show that BCR activation of lytic infection occurs not only in tumor cell lines but also in freshly isolated B cells from patients and that this activation can be blocked by BCR inhibitors.
Effectiveness of α2agonists for sedation in paediatric critical care: study protocol for a retrospective cohort observational study
Authors: Hayden John C , Dawkins Ian , Breatnach Cormac , Leacy Finbarr P , Foxton June , Healy Martina , Cousins Gráinne , Gallagher Paul J , Doherty Dermot R 
Published: June 2017

IntroductionMechanically ventilated children in paediatric intensive care units are commonly administered analgesics and sedative agents to minimise pain and distress and facilitate cooperation with medical interventions. Opioids and benzodiazepines are the most common analgesic and sedative agents but have safety concerns. The α2agonists clonidine and dexmedetomidine are alternative sedatives in use despite neither having robust evidence to support their use. Studies evaluating effectiveness of α2agonists to date have not focused on sedation-based outcomes instead focusing on opioid-sparing properties and ventilation outcomes. The aim of this study is to evaluate if an opioid-based sedation regimen, with an α2agonist adjunct (clonidine or dexmedetomidine), produces a non-inferior proportion of time adequately sedated compared with a control group without an α2agonist adjunct, while conferring potential additional benefits such as reduced opioid administration and less exposure to potential additional agents such as benzodiazepines.Methods and analysisWe will conduct a retrospective cohort study in two Irish paediatric intensive care units using clinical information on patient characteristics, sedation scores and drug use. Eligible children admitted between January 2014 and June 2016 who were mechanically ventilated and received an opioid infusion will be included. Patients will be categorised into two exposure categories (received an α2agonist or did not receive an α2agonist) and the time adequately sedated (measured using the COMFORT Behaviour Score) will be calculated using interpolation of nursing sedation scores at each recorded time point. At least 150 per group is planned for inclusion to ensure adequate study power. Propensity score matching will be used in analysis to account for potential confounding by indication.Ethics and disseminationThe study has been approved by the ethics committees of both hospitals. Dissemination will occur via local, national and international presentations for academic and healthcare audiences as well as through peer reviewed publications.
Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution
Authors: Chakrabarti Shaon , Michor Franziska 
Published: June 2017

Abstract
The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials. Cancer Res; 77(14); 3908–21. ©2017 AACR.
Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions
Authors: Porter Christopher C. , Druley Todd E. , Erez Ayelet , Kuiper Roland P. , Onel Kenan , Schiffman Joshua D. , Wolfe Schneider Kami , Scollon Sarah R. , Scott Hamish S. , Strong Louise C. , Walsh Michael F. , Nichols Kim E. 
Published: June 2017

Abstract
Leukemia, the most common childhood cancer, has long been recognized to occasionally run in families. The first clues about the genetic mechanisms underlying familial leukemia emerged in 1990 when Li-Fraumeni syndrome was linked to TP53 mutations. Since this discovery, many other genes associated with hereditary predisposition to leukemia have been identified. Although several of these disorders also predispose individuals to solid tumors, certain conditions exist in which individuals are specifically at increased risk to develop myelodysplastic syndrome (MDS) and/or acute leukemia. The increasing identification of affected individuals and families has raised questions around the efficacy, timing, and optimal methods of surveillance. As part of the AACR Childhood Cancer Predisposition Workshop, an expert panel met to review the spectrum of leukemia-predisposing conditions, with the aim to develop consensus recommendations for surveillance for pediatric patients. The panel recognized that for several conditions, routine monitoring with complete blood counts and bone marrow evaluations is essential to identify disease evolution and enable early intervention with allogeneic hematopoietic stem cell transplantation. However, for others, less intensive surveillance may be considered. Because few reports describing the efficacy of surveillance exist, the recommendations derived by this panel are based on opinion, and local experience and will need to be revised over time. The development of registries and clinical trials is urgently needed to enhance understanding of the natural history of the leukemia-predisposing conditions, such that these surveillance recommendations can be optimized to further enhance long-term outcomes. Clin Cancer Res; 23(11); e14–e22. ©2017 AACR.
See all articles in the online-only CCR Pediatric Oncology Series.
Reactivation of the p90RSK–CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G2–M Arrest and Mediates Acquired Resistance to Ganetespib inKRAS-Mutant NSCLC
Authors: Chatterjee Suman , Huang Eric H.-B. , Christie Ian , Burns Timothy F. 
Published: June 2017

AbstractA subset of non–small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations, including the most frequently observed driver mutant KRAS, which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Hsp90 inhibitors appeared to be a promising therapy for KRAS-mutant NSCLC; however, limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib, and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit. Here, we investigated the mechanism(s) of resistance to ganetespib and explored why the combination with docetaxel failed in the clinic. We have not only identified a critical role for the bypass of the G2–M cell-cycle checkpoint as a mechanism of ganetespib resistance (GR) but have also found that GR leads to cross-resistance to docetaxel. Reactivation of p90RSK and its downstream target, CDC25C, was critical for GR and mediated the bypass of a G2–M arrest. Overexpression of either p90RSK or CDC25C lead to bypass of G2–M arrest and induced ganetespib resistance in vitro and in vivo. Moreover, resistance was dependent on p90RSK/CDC25C signaling, as synthetic lethality to ERK1/2, p90RSK, or CDC25C inhibitors was observed. Importantly, the combination of ganetespib and p90RSK or CDC25C inhibitors was highly efficacious in parental cells. These studies provide a way forward for Hsp90 inhibitors through the development of novel rationally designed Hsp90 inhibitor combinations that may prevent or overcome resistance to Hsp90i. Mol Cancer Ther; 16(8); 1658–68. ©2017 AACR.
Microvesicles in vascular homeostasis and diseases
Authors: Ridger Victoria C. , Boulanger Chantal M. , Angelillo-Scherrer Anne , Badimon Lina , Blanc-Brude Olivier , Bochaton-Piallat Marie-Luce , Boilard Eric , Buzas Edit I. , Caporali Andreas , Dignat-George Francoise , Evans Paul C. , Lacroix Romaric , Lutgens Esther , Ketelhuth Daniel F. J. , Nieuwland Rienk , Toti Florence , Tuñon Jose , Weber Christian , Hoefer Imo E. , Lip Gregory Y. H. , Werner Nikos , Shantsila Eduard , ten Cate Hugo , Thomas Mark , Harrison Paul 
Published: June 2017

SummaryMicrovesicles are members of the family of extracellular vesicles shed from the plasma membrane of activated or apoptotic cells. Microvesicles were initially characterised by their pro-coagulant activity and described as “microparticles”. There is mounting evidence revealing a role for microvesicles in intercellular communication, with particular relevance to hemostasis and vascular biology. Coupled with this, the potential of microvesicles as meaningful biomarkers is under intense investigation. This Position Paper will summarise the current knowledge on the mechanisms of formation and composition of microvesicles of endothelial, platelet, red blood cell and leukocyte origin. This paper will also review and discuss the different methods used for their analysis and quantification, will underline the potential biological roles of these vesicles with respect to vascular homeostasis and thrombosis and define important themes for future research.
Is a normal computed tomography pulmonary angiography safe to rule out acute pulmonary embolism in patients with a likely clinical probability?
Authors: van der Hulle Tom , van Es Nick , den Exter Paul , van Es Josien , Mos Inge , Douma Renée , Kruip Marieke , Hovens Marcel , ten Wolde Marije , Nijkeuter Mathilde , ten Cate Hugo , Kamphuisen Pieter , Büller Harry , Huisman Menno , Klok Frederikus 
Published: June 2017

SummaryA normal computed tomography pulmonary angiography (CTPA) remains a controversial criterion for ruling out acute pulmonary embolism (PE) in patients with a likely clinical probability. We set out to determine the risk of VTE and fatal PE after a normal CTPA in this patient category and compare these risk to those after a normal pulmonary angiogram of 1.7% (95%CI 1.0–2.7%) and 0.3% (95%CI 0.02–0.7%). A patient-level meta-analysis from 4 prospective diagnostic management studies that sequentially applied the Wells rule, D-dimer tests and CTPA to consecutive patients with clinically suspected acute PE. The primary outcome was the 3-month VTE incidence after a normal CTPA. A total of 6,148 patients were included with an overall PE prevalence of 24%. The 3-month VTE incidence in all 4,421 patients in whom PE was excluded at baseline was 1.2% (95%CI 0.48–2.6) and the risk of fatal PE was 0.11% (95%CI 0.02–0.70). In patients with a likely clinical probability the 3-month incidences of VTE and fatal PE were 2.0% (95%CI 1.0–4.1%) and 0.48% (95%CI 0.20–1.1%) after a normal CTPA. The 3-month incidence of VTE was 6.3% (95%CI 3.0–12) in patients with a Wells rule >6 points. In conclusion, this study suggests that a normal CTPA may be considered as a valid diagnostic criterion to rule out PE in the majority of patients with a likely clinical probability, although the risk of VTE is higher in subgroups such as patients with a Wells rule >6 points for which a closer follow-up should be considered.Supplementary Material to this article is available online at www.thrombosis-online.com.
Outcome With the Repositionable and Retrievable Boston Scientific Lotus Valve Compared With the Balloon-Expandable Edwards Sapien 3 Valve in Patients Undergoing Transfemoral Aortic Valve Replacement
Authors: Seeger Julia , Gonska Birgid , Rottbauer Wolfgang , Wöhrle Jochen 
Published: June 2017

Background—
New generation devices for transfemoral aortic valve replacement were optimized on valve positioning and reduction of residual aortic regurgitation. We compared 30-day, 12-month, and 24-month outcomes of the Boston Scientific Lotus valve (Lotus) and the balloon-expandable Edwards Sapien 3 (ES3) valve. Primary end point was all-cause mortality or disabling stroke within 12 months.

Methods and Results—

Between 2014 and 2016, 537 patients were enrolled at our center, and 202 patients received Lotus and 335 ES3. There was no residual moderate or severe aortic regurgitation. Rate of mild aortic regurgitation was lower with the repositionable and retrievable Lotus valve compared with the ES3. Rate of pacemaker implantation was significantly higher with the Lotus valve compared with the ES3 valve (36.1% versus 14.9%,
P
<0.01). Valve Academic Research Consortium-2 early safety end point at 30 days was 7.4% with both devices with no difference in all-cause mortality (Lotus, 1.9%; ES3, 1.8%;
P
=0.87), rate of disabling stroke (Lotus, 1.5%; ES3, 2.1%;
P
=0.62), or major vascular complications (Lotus, 2.9%; ES3, 2.4%;
P
=0.69). The primary end point at 12 months was similar between groups. In a propensity score–matched comparison, there was no difference in the primary end point within 12 months (Lotus, 15.5%; ES3, 18.6%;
P
=0.69) and 24 months (Lotus, 21.9%; ES3, 26.4%;
P
=0.49).

Conclusions—
Transfemoral aortic valve replacement with the ES3 and the Lotus were associated with similar 30-day, 12-month, and 24-month clinical outcomes. Need for permanent pacemaker implantation was significantly higher with the repositionable Lotus device.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02162069.
Associations Between Adding a Radial Artery Graft to Single and Bilateral Internal Thoracic Artery Grafts and Outcomes
Authors: Taggart David P. , Altman Douglas G. , Flather Marcus , Gerry Stephen , Gray Alastair , Lees Belinda , Benedetto Umberto 
Published: June 2017

Background:
Whether the use of the radial artery (RA) can improve clinical outcomes in coronary artery bypass graft surgery remains unclear. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral internal thoracic artery (BITA) over single left internal thoracic artery (SITA). In the ART, a large proportion of patients (≈20%) also received an RA graft instead of a saphenous vein graft (SVG). We aimed to investigate the associations between using the RA instead of an SVG to supplement SITA or BITA grafts and outcomes by performing a post hoc analysis of the ART.

Methods:
Patients enrolled in the ART (n=3102) were classified on the basis of conduits actually received (as treated). The analysis included 2737 patients who received an RA graft (RA group; n=632) or SVG only (SVG group; n=2105) in addition to SITA or BITA grafts. The primary end point was the composite of myocardial infarction, cardiovascular death, and repeat revascularization at 5 years. Propensity score matching and stratified Cox regression were used to compare the 2 strategies.

Results:

Myocardial infarction, cardiovascular death, and repeat revascularization cumulative incidence was 2.3% (95% confidence interval [CI], 1.1–3.4), 3.5% (95% CI, 2.1–5.0), and 4.4% (95% CI, 2.8–6.0) in the RA group and 3.4% (95% CI, 2.0–4.8), 4.0% (95% CI, 2.5–5.6), and 7.6% (95% CI, 5.5–9.7) in the SVG group, respectively. The composite end point was significantly lower in the RA group (8.8%; 95% CI, 6.5–11.0) compared with the SVG group (13.6%; 95% CI, 10.8–16.3;
P
=0.005). This association was present when an RA graft was used to supplement both SITA and BITA grafts (interaction
P
=0.62).

Conclusions:
This post hoc ART analysis showed that an additional RA was associated with lower risk for midterm major adverse cardiac events when used to supplement SITA or BITA grafts.

Clinical Trial Registration:

URL:
https://www.situ.ox.ac.uk/surgical-trials/art
. Unique identifier: ISRCTN46552265.
Some Remarks about the Latin Physiologus Extracts Transmitted in the Liber Glossarum
Authors: Gorla Silvia 
Published: June 2017

Abstract
This paper is aimed at describing the presence of the Latin Physiologus in the Liber Glossarum. After a brief introduction to the Latin Physiologus and a census of the Liber Glossarum items drawn on it, two noteworthy attitudes of the Liber Glossarum are outlined: distrust in the Physiologus stories, clearly expressed at least for the items up to section FE, and no interest in allegorical and moral comments. Finally, a couple of Liber Glossarum entries from the Latin Physiologus (AS 171 Aspides, PE 217 Pelicanus) are analysed in comparison with the text given directly by the existing versions of the Latin Physiologus: the Liber Glossarum comes out as an important means of transmission of ancient stages of the Latin Physiologus text which would be otherwise lost.
Immune Checkpoint Inhibition and the Prevalence of Autoimmune Disorders Among Patients With Lung and Renal Cancer
Authors: El-Refai Sherif M , Brown Joshua D , Black Esther P , Talbert Jeffery C 
Published: June 2017

Purpose: Immune checkpoint inhibition reactivates the immune response against cancer cells in multiple tissue types and has been shown to induce durable responses. However, for patients with autoimmune disorders, their conditions can worsen with this reactivation. We sought to identify, among patients with lung and renal cancer, how many harbor a comorbid autoimmune condition and may be at risk of worsening their condition while on immune checkpoint inhibitors such as nivolumab and pembrolizumab. Methods: An administrative health care claims database, Truven MarketScan, was used to identify patients diagnosed with lung and renal cancer from 2010 to 2013. We assessed patients for diagnosis of autoimmune diseases 1 year prior to or after diagnosis of cancer using International Classification of Diseases, Ninth Revision codes for 41 autoimmune diseases. Baseline characteristics and other comorbid conditions were recorded. Results: More than 25% of patients with both lung and renal cancer had a comorbid autoimmune condition between 2010 and 2013 and were more likely to be women, older, and have more baseline comorbidities. Conclusions: This population presents a dilemma to physicians when deciding to treat with immune checkpoint inhibitors and risk immune-related adverse events. Future evaluation of real-world use of immune checkpoint inhibitors in patients with cancer with autoimmune diseases will be needed.