bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Peptidoglycan Hydrolase Constructs with Synergistic Staphylolytic Activity in Cow's Milk
Authors: Verbree Carolin T. , Dätwyler Steven M. , Meile Susanne , Eichenseher Fritz , Donovan David M. , Loessner Martin J. , Schmelcher Mathias 
Published: February 2017

ABSTRACT

Peptidoglycan hydrolases (PGHs) have been suggested as novel therapeutics for the treatment of bovine mastitis. However, activity in the presence of cow's milk is an important requirement for drugs administered into the bovine udder. We have screened a library of >170 recombinant PGHs, including engineered bacteriophage endolysins, for enzymes with activity against
Staphylococcus aureus
in milk, using a microtiter plate-based protocol. Nine suitable PGH constructs were identified by this approach and further compared in time-kill assays for their efficacy against
S. aureus
in heat-treated milk. The three most active enzymes (lysostaphin, Ami2638A, and CHAPK_CWT-LST) reduced
S. aureus
in milk to undetectable numbers within minutes at nanomolar concentrations. Due to their different peptidoglycan cleavage sites, these PGH constructs revealed synergistic activity in most combinations, as demonstrated by checkerboard assays, spot assays, and time-kill experiments. Furthermore, they proved active against a selection of staphylococcal mastitis isolates from different geographical regions when applied individually or in synergistic combination. The most effective PGH combination completely eradicated
S. aureus
from milk, with no more bacteria being detected within 24 h after addition of the enzymes, corresponding to a reduction of >9 log units compared to the control. Efficacy was also retained at different inoculum levels (3 versus 6 log CFU/ml) and when
S. aureus
was grown in milk as opposed to broth prior to the experiments. In raw cow's milk, CHAPK_CWT-LST showed reduced efficacy, whereas both Ami2638A and lysostaphin retained their activity, reducing bacterial numbers by >3.5 log units within 3 h.

IMPORTANCE
Staphylococci and
S. aureus
in particular are a major cause of bovine mastitis, an inflammation of the mammary gland in cows associated with high costs and risks for consumers of milk products.
S. aureus
-induced mastitis, commonly treated by intramammary infusion of antibiotics, is characterized by low cure rates and increasing antibiotic resistance in bacteria. Therefore, alternative treatment options are highly desirable. PGHs, including bacteriophage endolysins, rapidly and specifically kill selected pathogens by degrading their cell wall and are refractory to resistance development, therefore holding promise as novel antibacterial agents. This study employed a screening approach to identify PGH constructs with high staphylolytic activity in cow's milk within a large collection of enzymes. Our results suggest that the most promising enzymes identified by this strategy hold potential as novel mastitis therapeutics and support their further characterization in animal models.
Dating Icelandic glacial floods using a new viscous remanent magnetization protocol
Authors: Berndt Thomas , Muxworthy Adrian R. 
Published: February 2017

Abstract
A new protocol using the viscous remanent magnetization (VRM) of boulders to date cataclysmic geological events such as tsunamis, glacial floods, and landslides is presented and its performance is assessed against two jökulhlaups (glacial floods) of known age in Iceland. High-intensity jökulhlaups have the ability to break off large boulders from bedrock and emplace and rotate them. These rocks originally carried a remanent magnetization parallel to the geomagnetic field during their formation. After being rotated by the flood, they acquire a VRM parallel with Earth’s magnetic field. In continuous thermal demagnetization experiments the unblocking temperature of the VRM can be determined, and subsequent rock magnetic VRM acquisition experiments can be used to establish a relationship between the unblocking temperature and the acquisition time, from which the time since the flood can be determined. The protocol was tested on 44 boulders from 2 historical jökulhlaups in Iceland and found to yield good order-of-magnitude estimates: 72 yr (confidence limits 11–360 yr) versus known 155 yr at the Sólheimajökull jökulhlaup and 290 yr (confidence limits 80–2300 yr) versus known 288 yr for the Kotarjökull jökulhlaup. The method can therefore be a valuable tool for future dating of cataclysmic events.
How to make a 350-m-thick lowstand systems tract in 17,000 years: The Late Pleistocene Po River (Italy) lowstand wedge
Authors: Pellegrini Claudio , Maselli Vittorio , Gamberi Fabiano , Asioli Alessandra , Bohacs Kevin M. , Drexler Tina M. , Trincardi Fabio 
Published: February 2017

Abstract
The 350-m-thick succession of the Po River lowstand wedge (Italy) associated with the Last Glacial Maximum (deposited over ∼17 k.y) contains stratal architecture at a physical scale commonly attributed to much longer time scales, with complex, systematically varying internal clinothem characteristics. This study investigated clinothem stacking patterns and controls through the integration of seismic reflection data with sediment attributes, micropaleontology, regional climate, eustacy, and high-resolution age control possible only in Quaternary sequences. Three clinothem types are differentiated based on topset geometry, shelf-edge and onlap-point trajectory, internal seismic facies, and interpreted bottomset deposits: type A has moderate topset aggradation, ascending shelf-edge trajectory, and mass-transport bottomset deposits; type B has eroded topset, descending shelf-edge trajectory, and bottomset distributary channel-lobe complexes; and type C has maximal topset aggradation, ascending shelf-edge trajectory, and concordant bottomsets. Type A and C clinothems exhibit reduced sediment bypass and delivery to the basin, whereas type B clinothems are associated with short intervals of increased sediment export from the shelf to deeper water. Clinothems individually span a range of 0.4–4.7 k.y., contemporaneous with significant eustatic and climate changes, but their stacking patterns resemble those found in ancient successions and ascribed to significantly longer durations, indicating that (1) the response time of ancient continental margin–scale systems to high-frequency variations in accommodation and sediment supply could be as short as centuries, (2) even millennial- to centennial-scale stratal units can record substantial influence of allogenic controls, and (3) sandy deposits can be compartmentalized even in a short-duration lowstand systems tract.
Approaching confidentiality at a familial level in genomic medicine: a focus group study with healthcare professionals
Authors: Dheensa Sandi , Fenwick Angela , Lucassen Anneke 
Published: February 2017

ObjectivesClinical genetics guidelines from 2011 conceptualise genetic information as confidential to families, not individuals. The normative consequence of this is that the family's interest is the primary consideration and genetic information is shared unless there are good reasons not to do so. We investigated healthcare professionals' (HCPs') views about, and reasoning around, individual and familial approaches to confidentiality and how such views influenced their practice.Method16 focus groups with 80 HCPs working in/with clinical genetics services were analysed, drawing on grounded theory.ResultsParticipants raised seven problems with, and arguments against, going beyond the individual approach to confidentiality. These problems fell into two overlapping categories: ‘relationships’ and ‘structures’. Most participants had never considered ways to—or thought it was impossible to—treat familial genetic information and personal information differently. They worried that putting the familial approach into practice could disrupt family dynamics and erode patient trust in the health service. They also thought they had insufficient resources to share information and feared that sharing might change the standard of care and make them more vulnerable to liability.ConclusionsA familial approach to confidentiality has not been accepted or adopted as a standard, but wider research suggests that some of the problems HCPs perceived are surmountable and sharing in the interest of the family can be achieved. However, further research is needed to explore how personal and familial genetic information can be separated in practice. Our findings are relevant to HCPs across health services who are starting to use genome tests as part of their routine investigations.
Effects of pulmonary rehabilitation in lung transplant candidates: a systematic review
Authors: Hoffman Mariana , Chaves Gabriela , Ribeiro-Samora Giane Amorim , Britto Raquel Rodrigues , Parreira Verônica Franco 
Published: February 2017

ObjectivesThe aim of this systematic review of randomised controlled trials (RCTs), and quasi-experimental and retrospective studies is to investigate the effects of pulmonary rehabilitation (PR) in patients with advanced chronic disease on the waiting list for lung transplantation.SettingPR performed for inpatient or outpatient lung transplant candidates.InterventionPR programme including aerobic exercise training and/or resistance exercise training.Primary and secondary outcomesQuality of life and exercise capacity (primary outcomes). Survival rate after transplant surgery; pulmonary function; respiratory muscle strength; psychological aspects; upper and lower extremity muscle strength and adverse effects (secondary outcomes). Two review authors independently selected the studies, assessed study quality and extracted data. Studies in any language were included.ResultsThis was a systematic review and studies were searched on the Cochrane Library, MEDLINE, EMBASE, CINAHL and PEDro. Experimental and retrospective studies evaluating the effects of PR in candidates for lung transplantation (>18 years old) with any lung diseases were included. 2 RCTs, and two quasi-experimental and two retrospectives studies, involving 1305 participants were included in the review. 5 studies included an enhancement reported in quality of life using the Short Form 36 questionnaire and showed improvements in some domains. All studies included exercise capacity evaluated through 6 min walk test and in five of them, there were improvements in this outcome after PR. Owing to the different characteristics of the studies, it was not possible to perform a meta-analysis.ConclusionsStudies included in this review showed that PR is an effective treatment option for patients on the waiting list for lung transplantation and can improve quality of life and exercise capacity in those patients. Although individual studies reported positive effects of PR, this review shows that there is a need for more studies of a high methodological quality addressing PR effects in lung transplant candidates.Trial registration numberPROSPERO CDR42015025110.
The edges of the wedges: a systematic approach to trap definition and risking for stratigraphic, combination and sub-unconformity traps
Authors: Stirling Eleanor J. , Fugelli Edith M. G. , Thompson Mark 
Published: February 2017

Abstract
In recent years, stratigraphic and combination traps such as Buzzard (UK North Sea) and Jubilee (Ghana) have attracted much industry attention. Such trap types are generally considered higher risk than structural traps, and understanding them represents a challenge for explorers, as numerous less successful (often amplitude-driven) attempts have demonstrated. Owing to their perceived high risk, stratigraphic traps are often drilled late in a basin's exploration history; however, we assert that consideration of stratigraphic traps should be part of any frontier exploration programme because they occur in all basin types and depositional settings, and allow new plays to be opened up. Additionally, stratigraphic, combination and sub-unconformity traps offer the chance to rejuvenate exploration in mature basins, as recent discoveries like the Edvard Grieg Field (Norwegian North Sea) have shown.
Focusing on clastic systems, and using a combination of seismic examples and models, we present two aspects of stratigraphic trap exploration: (1) the regional and local factors that favour the development of stratigraphic trap edges; and (2) a systematic method for defining and risking the trap edges, avoiding the common problem of over-risking. These two methods, used together and applied consistently, allow explorers to focus on the right area of a basin and to risk stratigraphic traps appropriately, for a fair comparison with structural traps.
Temozolomide in the Era of Precision Medicine
Authors: Thomas Anish , Tanaka Mamoru , Trepel Jane , Reinhold William C. , Rajapakse Vinodh N. , Pommier Yves 
Published: February 2017

Abstract
In the January 1, 2017, issue of Cancer Research, Nagel and colleagues demonstrate the value of assays that determine the DNA repair capacity of cancers in predicting response to temozolomide. Using a fluorescence-based multiplex flow cytometric host cell reactivation assay that provides simultaneous readout of DNA repair capacity across multiple pathways, they show that the multivariate drug response models derived from cell line data were applicable to patient-derived xenograft models of glioblastoma. In this commentary, we first outline the mechanism of activity and current clinical application of temozolomide, which, until now, has been largely limited to glioblastoma. Given the challenges of clinical application of functional assays, we argue that functional readouts be approximated by genomic signatures. In this context, a combination of MGMT activity and mismatch repair (MMR) status of the tumor are important parameters that determine sensitivity to temozolomide. More reliable methods are needed to determine MGMT activity as DNA methylation, the current standard, does not accurately reflect the expression of MGMT. Also, genomics for MMR are warranted. Furthermore, based on patterns of MGMT expression across different solid tumors, we make a case for revisiting temozolomide use in a broader spectrum of cancers based on our current understanding of its molecular basis of activity. Cancer Res; 77(4); 823–6. ©2017 AACR.
Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study
Authors: Ramanathan Ramesh K. , Korn Ronald L. , Raghunand Natarajan , Sachdev Jasgit C. , Newbold Ronald G. , Jameson Gayle , Fetterly Gerald J. , Prey Joshua , Klinz Stephan G. , Kim Jaeyeon , Cain Jason , Hendriks Bart S. , Drummond Daryl C. , Bayever Eliel , Fitzgerald Jonathan B. 
Published: February 2017

AbstractPurpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI).Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2* signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI.Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P &lt; 0.001 at 1 hour and P &lt; 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman ρ = 0.7824; P = 0.0016).Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors. Clin Cancer Res; 23(14); 3638–48. ©2017 AACR.
Bevacizumab May Differentially Improve Ovarian Cancer Outcome in Patients with Proliferative and Mesenchymal Molecular Subtypes
Authors: Kommoss Stefan , Winterhoff Boris , Oberg Ann L. , Konecny Gottfried E. , Wang Chen , Riska Shaun M. , Fan Jian-Bing , Maurer Matthew J. , April Craig , Shridhar Viji , Kommoss Friedrich , du Bois Andreas , Hilpert Felix , Mahner Sven , Baumann Klaus , Schroeder Willibald , Burges Alexander , Canzler Ulrich , Chien Jeremy , Embleton Andrew C. , Parmar Mahesh , Kaplan Richard , Perren Timothy , Hartmann Lynn C. , Goode Ellen L. , Dowdy Sean C. , Pfisterer Jacobus 
Published: February 2017

Abstract
Purpose: Recent progress in understanding the molecular biology of epithelial ovarian cancer has not yet translated into individualized treatment for these women or improvements in their disease outcome. Gene expression has been utilized to identify distinct molecular subtypes, but there have been no reports investigating whether or not molecular subtyping is predictive of response to bevacizumab in ovarian cancer.
Experimental Design: DASL gene expression arrays were performed on FFPE tissue from patients enrolled on the ICON7 trial. Patients were stratified into four TCGA molecular subtypes. Associations between molecular subtype and the efficacy of randomly assigned therapy with bevacizumab were assessed.
Results: Molecular subtypes were assigned as follows: 122 immunoreactive (34%), 96 proliferative (27%), 73 differentiated (20%), and 68 mesenchymal (19%). In univariate analysis patients with tumors of proliferative subtype obtained the greatest benefit from bevacizumab with a median PFS improvement of 10.1 months [HR, 0.55 (95% CI, 0.34–0.90), P = 0.016]. For the mesenchymal subtype, bevacizumab conferred a nonsignificant improvement in PFS of 8.2 months [HR 0.78 (95% CI, 0.44–1.40), P = 0.41]. Bevacizumab conferred modest improvements in PFS for patients with immunoreactive subtype (3.8 months; P = 0.08) or differentiated subtype (3.7 months; P = 0.61). Multivariate analysis demonstrated significant PFS improvement in proliferative subtype patients only [HR, 0.45 (95% CI, 0.27–0.74), P = 0.0015].
Conclusions: Ovarian carcinoma molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment that includes bevacizumab. Validation of our findings in an independent cohort could enable the use of bevacizumab for those patients most likely to benefit, thereby reducing side effects and healthcare cost. Clin Cancer Res; 23(14); 3794–801. ©2017 AACR.
Healthcare Resource Availability, Quality of Care, and Acute Ischemic Stroke Outcomes
Authors: O'Brien Emily C. , Wu Jingjing , Zhao Xin , Schulte Phillip J. , Fonarow Gregg C. , Hernandez Adrian F. , Schwamm Lee H. , Peterson Eric D. , Bhatt Deepak L. , Smith Eric E. 
Published: February 2017

Background
Healthcare resources vary geographically, but associations between hospital‐based resources and acute stroke quality and outcomes remain unclear.

Methods and Results
Using Get With The Guidelines‐Stroke and Dartmouth Atlas of Health Care data, we examined associations between healthcare resource availability, stroke care, and outcomes. We categorized hospital referral regions with high‐, medium‐, or low‐resource levels based on the 2006 national per‐capita availability median of 6 relevant acute stroke care resources. Using multivariable logistic regression, we examined healthcare resource level and in‐hospital quality and outcomes. Of 1 480 308 admitted ischemic stroke patients (2006–2013), 28.8% were hospitalized in low‐, 44.4% in medium‐, and 26.9% in high‐resource hospital referral regions. Quality‐of‐care/timeliness metrics, adjusted length of stay, and in‐hospital mortality were similar across all resource levels.

Conclusions
Significant variation exists in regional availability of healthcare resources for acute ischemic stroke treatment, yet among Get With the Guidelines‐Stroke hospitals, quality of care and in‐hospital outcomes did not differ by regional resource availability.
Novel Thrombolytic Drug Based on Thrombin Cleavable Microplasminogen Coupled to a Single‐Chain Antibody Specific for Activated GPIIb/IIIa
Authors: Bonnard Thomas , Tennant Zachary , Niego Be'Eri , Kanojia Ruchi , Alt Karen , Jagdale Shweta , Law Lok Soon , Rigby Sheena , Medcalf Robert Lindsay , Peter Karlheinz , Hagemeyer Christoph Eugen 
Published: February 2017

Background

Thrombolytic therapy for acute thrombosis is limited by life‐threatening side effects such as major bleeding and neurotoxicity. New treatment options with enhanced fibrinolytic potential are therefore required. Here, we report the development of a new thrombolytic molecule that exploits key features of thrombosis. We designed a recombinant microplasminogen modified to be activated by the prothrombotic serine‐protease thrombin (HtPlg), fused to an activation‐specific anti–glycoprotein IIb/
III
a single‐chain antibody (
SCE
5), thereby hijacking the coagulation system to initiate thrombolysis.

Methods and Results

The resulting fusion protein named
SCE
5‐HtPlg shows in vitro targeting towards the highly abundant activated form of the fibrinogen receptor glycoprotein IIb/
III
a expressed on activated human platelets. Following thrombin formation,
SCE
5‐HtPlg is activated to contain active microplasmin. We evaluate the effectiveness of our targeted thrombolytic construct in two models of thromboembolic disease. Administration of
SCE
5‐HtPlg (4 μg/g body weight) resulted in effective thrombolysis 20 minutes after injection in a ferric chloride–induced model of mesenteric thrombosis (48±3% versus 92±5% for saline control,
P
<0.01) and also reduced emboli formation in a model of pulmonary embolism (
P
<0.01 versus saline). Furthermore, at these effective therapeutic doses, the
SCE
5‐HtPlg did not prolong bleeding time compared with saline (
P
=0.99).

Conclusions
Our novel fusion molecule is a potent and effective treatment for thrombosis that enables in vivo thrombolysis without bleeding time prolongation. The activation of this construct by thrombin generated within the clot itself rather than by a plasminogen activator, which needs to be delivered systemically, provides a novel targeted approach to improve thrombolysis.