bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining a Novel Role for the Coxsackievirus and Adenovirus Receptor in Human Adenovirus Serotype 5 Transduction
In Vitro
in the Presence of Mouse Serum
Authors: Lopez-Gordo Estrella , Doszpoly Andor , Duffy Margaret R. , Coughlan Lynda , Bradshaw Angela C. , White Katie M. , Denby Laura , Nicklin Stuart A. , Baker Andrew H. 
Published: April 2017

ABSTRACT

Human adenoviral serotype 5 (HAdV-5) vectors have predominantly hepatic tropism when delivered intravascularly, resulting in immune activation and toxicity. Coagulation factor X (FX) binding to HAdV-5 mediates liver transduction and provides protection from virion neutralization in mice. FX is dispensable for liver transduction in mice lacking IgM antibodies or complement, suggesting that alternative transduction pathways exist. To identify novel factor(s) mediating HAdV-5 FX-independent entry, we investigated HAdV-5 transduction
in vitro
in the presence of serum from immunocompetent C57BL/6 or immunocompromised mice lacking IgM antibodies (Rag 2
−/−
and NOD-scid-gamma [NSG]). Sera from all three mouse strains enhanced HAdV-5 transduction of A549 cells. While inhibition of HAdV-5–FX interaction with FX-binding protein (X-bp) inhibited transduction in the presence of C57BL/6 serum, it had negligible effect on the enhanced transduction observed in the presence of Rag 2
−/−
or NSG serum. Rag 2
−/−
serum also enhanced transduction of the FX binding-deficient HAdV-5HVR5*HVR7*E451Q (AdT*). Interestingly, Rag 2
−/−
serum enhanced HAdV-5 transduction in a FX-independent manner in CHO-CAR and SKOV3-CAR cells (CHO or SKOV3 cells transfected to stably express human coxsackievirus and adenovirus receptor [CAR]). Additionally, blockade of CAR with soluble HAdV-5 fiber knob inhibited mouse serum-enhanced transduction in A549 cells, suggesting a potential role for CAR. Transduction of HAdV-5 KO1 and HAdV-5/F35 (CAR binding deficient) in the presence of Rag 2
−/−
serum was equivalent to that of HAdV-5, indicating that direct interaction between HAdV-5 and CAR is not required. These data suggest that FX may protect HAdV-5 from neutralization but has minimal contribution to HAdV-5 transduction in the presence of immunocompromised mouse serum. Alternatively, transduction occurs via an unidentified mouse serum protein capable of bridging HAdV-5 to CAR.

IMPORTANCE
The intravascular administration of HAdV-5 vectors can result in acute liver toxicity, transaminitis, thrombocytopenia, and injury to the vascular endothelium, illustrating challenges yet to overcome for HAdV-5-mediated systemic gene therapy. The finding that CAR and potentially an unidentified factor present in mouse serum might be important mediators of HAdV-5 transduction highlights that a better understanding of the complex biology defining the interplay between adenovirus immune recognition and cellular uptake mechanisms is still required. These findings are important to inform future optimization and development of HAdV-5-based adenoviral vectors for gene therapy.
Ages of Norwegian oils and bitumen based on age-specific biomarkers
Authors: Matapour Z. , Karlsen D. A. 
Published: April 2017

Norwegian oils are generally considered sourced primarily from the Kimmeridge Clay equivalent shales such as the Draupne, Mandal, Spekk and Hekkingen formations, with secondary contributions from the mid–lower Jurassic, and also from the Triassic in the Barents Sea (Botneheia Formation). Still, as most of our age inferences concerning source-oil correlation are based on facies-specific biomarkers, a number of proposed correlations have been questioned.
Thus, source to oil correlations were frequently made on the basis of facies parameters, and rightfully so, but facies-specific signatures in oils will transgress age – and, in principle, not correlate with the phylogenetic evolution. This means that one could, in principle assign an oil to ‘the wrong’ age – when one is, in fact, linking it to a known source rock signature.
A series of 40 oil samples and core extracts, which cover a wide range both stratigraphically and geographically, have been analysed. In this paper, we present for the first time a Norwegian oil-age map based on age-specific biomarkers among the nordiacholestanes and triaromatic steroids parameters, and delineate also where we find Cretaceous- and Palaeozoic-derived oils. The reasons for this distribution pattern, compared to that of Mesozoic oils on the Norwegian Continental Shelf (NCS), are discussed.
Developmental profile of motor cortex transcallosal inhibition in children and adolescents
Authors: Ciechanski Patrick , Zewdie Ephrem , Kirton Adam 
Published: April 2017

Transcallosal fibers facilitate interhemispheric networks involved in motor tasks. Despite their clinical relevance, interhemispheric motor control systems have not been completely defined in the developing brain. The objective of this study was to examine the developmental profile of transcallosal inhibition in healthy children and adolescents. Nineteen typically developing right-handed participants were recruited. Two transcranial magnetic stimulation (TMS) paradigms assessed transcallosal inhibition: ipsilateral silent periods (iSP) and paired-pulse interhemispheric inhibition (IHI). TMS was applied to the motor hotspot of the first dorsal interosseous muscle. Resting motor threshold (RMT), iSP latency, duration and suppression strength, and paired-pulse IHI were measured from both hemispheres. The Purdue Pegboard Test assessed unimanual motor function. Hemispheric differences were evident for RMT and iSP latency and suppression strength, where the left hemisphere had a lower RMT, prolonged latency, and greater suppression strength. iSP duration showed hemispheric symmetry. RMT and iSP latency decreased with age, whereas iSP suppression strength increased. Girls showed shorter iSP latency. Children typically displayed IHI, although hemispheric differences were observed. iSP suppression strength was uniquely associated with IHI within individuals. iSP duration correlated with motor performance. TMS can characterize transcallosal inhibition in normal children and adolescents with effects of age, directionality, sex, and motor performance. Establishing this developmental profile of interhemispheric interactions may advance understanding and therapeutic strategies for pediatric motor disorders such as cerebral palsy. NEW & NOTEWORTHY Here we demonstrate that transcranial magnetic stimulation can characterize transcallosal inhibition in normal children and adolescents with effects of age, directionality, handedness, and motor performance. Interestingly, we also demonstrated sex effects, possibly related to the differing developmental profiles of boys and girls. Establishing this developmental profile of interhemispheric interactions may advance understanding and therapeutic strategies for pediatric motor disorders such as cerebral palsy.
A Phase 2/3 Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Lenalidomide Versus Investigator's Choice in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Authors: Czuczman Myron S. , Trněný Marek , Davies Andrew , Rule Simon , Linton Kim M. , Wagner-Johnston Nina , Gascoyne Randy D. , Slack Graham W. , Brousset Pierre , Eberhard David A. , Hernandez-Ilizaliturri Francisco J. , Salles Gilles , Witzig Thomas E. , Zinzani Pier Luigi , Wright George W. , Staudt Louis M. , Yang Yandan , Williams P. Mickey , Lih Chih-Jian , Russo Jacqueline , Thakurta Anjan , Hagner Patrick , Fustier Pierre , Song Dale , Lewis Ian D. 
Published: April 2017

Abstract
Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints.
Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550).
Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127–37. ©2017 AACR.
Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells
Authors: Dosier Laura Beth Mann , Premkumar Vikram J. , Zhu Hongmei , Akosman Izzet , Wempe Michael F. , McMahon Timothy J. 
Published: April 2017

SummaryThe system L neutral amino acid transporter (LAT; LAT1, LAT2, LAT3, or LAT4) has multiple functions in human biology, including the cellular import of S-nitrosothiols (SNOs), biologically active derivatives of nitric oxide (NO). SNO formation by haemoglobin within red blood cells (RBC) has been studied, but the conduit whereby a SNO leaves the RBC remains unidentified. Here we hypothesised that SNO export by RBCs may also depend on LAT activity, and investigated the role of RBC LAT in modulating SNO-sensitive RBC-endothelial cell (EC) adhesion. We used multiple pharmacologic inhibitors of LAT in vitro and in vivo to test the role of LAT in SNO export from RBCs and in thereby modulating RBC-EC adhesion. Inhibition of human RBC LAT by type-1-specific or nonspecific LAT antagonists increased RBC-endothelial adhesivity in vitro, and LAT inhibitors tended to increase post-transfusion RBC sequestration in the lung and decreased oxygenation in vivo. A LAT1-specific inhibitor attenuated SNO export from RBCs, and we demonstrated LAT1 in RBC membranes and LAT1 mRNA in reticulocytes. The proadhesive effects of inhibiting LAT1 could be overcome by supplemental L-CSNO (S-nitroso-L-cysteine), but not D-CSNO or L-Cys, and suggest a basal anti-adhesive role for stereospecific intercellular SNO transport. This study reveals for the first time a novel role of LAT1 in the export of SNOs from RBCs to prevent their adhesion to ECs. The findings have implications for the mechanisms of intercellular SNO signalling, and for thrombosis, sickle cell disease, and post-storage RBC transfusion, when RBC adhesivity is increased.
Delayed-onset of procoagulant signalling revealed by kinetic analysis of COAT platelet formation
Authors: Alberio Lorenzo , Ravanat Catherine , Hechler Béatrice , Mangin Pierre H. , Lanza François , Gachet Christian 
Published: April 2017

SummaryThe combined action of collagen and thrombin induces the formation of COAT platelets, which are characterised by a coat of procoagulant and adhesive molecules on their surface. Although recent work has started to highlight their clinical relevance, the exact mechanisms regulating the formation of procoagulant COAT platelets remain unclear. Therefore, we employed flow cytometry in order to visualise in real time surface and intracellular events following simultaneous platelet activation with convulxin and thrombin. After a rapid initial response pattern characterised by the homogenous activation of the fibrinogen receptor glycoprotein IIb/IIIa in all platelets, starting with a delay of about 2 minutes an increasing fraction transforms to procoagulant COAT platelets. Their surface is characterised by progressive loss of PAC-1 binding, expression of negative phospholipids and retention of α-granule von Willebrand factor. Intracellular events in procoagulant COAT platelets are a marked increase of free calcium into the low micromolar range, concomitantly with early depolarisation of the mitochondrial membrane and activation of caspase-3, while non-COAT platelets keep the intracellular free calcium in the nanomolar range and maintain an intact mitochondrial membrane. We show for the first time that the flow-cytometrically distinct fractions of COAT and non-COAT platelets differentially phosphorylate two signalling proteins, PKCα and p38MAPK, which may be involved in the regulation of the different calcium fluxes observed in COAT versus non-COAT platelets. This study demonstrates the utility of concomitant cellular and signalling evaluation using flow cytometry in order to further dissect the mechanisms underlying the dichotomous platelet response observed after collagen/thrombin stimulation.Supplementary Material to this article is available online at www.thrombosis-online.com.
Fibrin clot characteristics in acute ischaemic stroke patients treated with thrombolysis: the impact on clinical outcome
Authors: Bembenek Jan P. , Niewada Maciej , Siudut Jakub , Plens Krzysztof , Członkowska Anna , Undas Anetta 
Published: April 2017

SummaryFibrin clot properties in acute ischaemic stroke (AIS) are unfavourably altered, including faster formation of denser and poorly lysable fibre networks. We investigated clot properties in AIS patients treated with recombinant tissue plasminogen activator (rtPA) and their impact on clinical outcome. In 74 consecutive AIS patients eligible for rtPA treatment, we assessed ex vivo plasma fibrin clot formation, permeability (Ks), and rtPA-induced lysis, along with peak thrombin generation, fibrinolysis proteins and inhibitors at three time points – on admission, after 24 hours and 3 months since stroke. Clinical outcome was assessed using the NIHSS and mRS scores. Compared with the pretreatment values, fibrin networks assessed 24 hours since thrombolysis were formed more slowly (+20.5 % lag phase on turbidimetry), were less compact (+36.9 % Ks), composed of thinner fibres (-10.6 % lower maximum absorbancy [ΔAb]), which were lysed more rapidly (-20.8 % clot lysis time [CLT] and +7.1 % the rate of rtPA-induced D-dimer release from clots [D-Drate]). Thrombin generation and fibrinolysis proteins remained elevated. Lower ΔAb (<0.86 at 405 nm), shorter CLT (<105 min), and higher D-Drate (>0.072 mg/l/min) assessed at baseline predicted good outcome (mRS 0–2) at 3 months after adjustment for age and fibrinogen. Logistic regression adjusted for potential confounders showed that good outcome at 3 months was predicted by pretreatment D-Drate, while pretreatment CLT predicted excellent outcome (mRS of 0–1). In conclusion, formation of denser fibrin clots displaying impaired lysability and pattern of their changes induced by thrombolysis may affect clinical outcome in AIS patients.
SOX17 Regulates Conversion of Human Fibroblasts Into Endothelial Cells and Erythroblasts by Dedifferentiation Into CD34
+
Progenitor Cells
Authors: Zhang Lianghui , Jambusaria Ankit , Hong Zhigang , Marsboom Glenn , Toth Peter T. , Herbert Brittney-Shea , Malik Asrar B. , Rehman Jalees 
Published: April 2017

Background:
The mechanisms underlying the dedifferentiation and lineage conversion of adult human fibroblasts into functional endothelial cells have not yet been fully defined. Furthermore, it is not known whether fibroblast dedifferentiation recapitulates the generation of multipotent progenitors during embryonic development, which give rise to endothelial and hematopoietic cell lineages. Here we established the role of the developmental transcription factor SOX17 in regulating the bilineage conversion of fibroblasts by the generation of intermediate progenitors.

Methods:

CD34
+
progenitors were generated after the dedifferentiation of human adult dermal fibroblasts by overexpression of pluripotency transcription factors. Sorted CD34
+
cells were transdifferentiated into induced endothelial cells and induced erythroblasts using lineage-specific growth factors. The therapeutic potential of the generated cells was assessed in an experimental model of myocardial infarction.

Results:

Induced endothelial cells expressed specific endothelial cell surface markers and also exhibited the capacity for cell proliferation and neovascularization. Induced erythroblasts expressed erythroid surface markers and formed erythroid colonies. Endothelial lineage conversion was dependent on the upregulation of the developmental transcription factor SOX17, whereas suppression of SOX17 instead directed the cells toward an erythroid fate. Implantation of these human bipotential CD34
+
progenitors into nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice resulted in the formation of microvessels derived from human fibroblasts perfused with mouse and human erythrocytes. Endothelial cells generated from human fibroblasts also showed upregulation of telomerase. Cell implantation markedly improved vascularity and cardiac function after myocardial infarction without any evidence of teratoma formation.

Conclusions:

Dedifferentiation of fibroblasts to intermediate CD34
+
progenitors gives rise to endothelial cells and erythroblasts in a SOX17-dependent manner. These findings identify the intermediate CD34
+
progenitor state as a critical bifurcation point, which can be tuned to generate functional blood vessels or erythrocytes and salvage ischemic tissue.
Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction
Authors: Obokata Masaru , Reddy Yogesh N.V. , Pislaru Sorin V. , Melenovsky Vojtech , Borlaug Barry A. 
Published: April 2017

Background:
Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. Phenotyping patients into pathophysiologically homogeneous groups may enable better targeting of treatment. Obesity is common in HFpEF and has many cardiovascular effects, suggesting that it may be a viable candidate for phenotyping. We compared cardiovascular structure, function, and reserve capacity in subjects with obese HFpEF, those with nonobese HFpEF, and control subjects.

Methods:

Subjects with obese HFpEF (body mass index ≥35 kg/m
2
; n=99), nonobese HFpEF (body mass index <30 kg/m
2
; n=96), and nonobese control subjects free of HF (n=71) underwent detailed clinical assessment, echocardiography, and invasive hemodynamic exercise testing.

Results:

Compared with both subjects with nonobese HFpEF and control subjects, subjects with obese HFpEF displayed increased plasma volume (3907 mL [3563–4333 mL] versus 2772 mL [2555–3133 mL], and 2680 mL [2380–3006 mL];
P
<0.0001), more concentric left ventricular remodeling, greater right ventricular dilatation (base, 34±7 versus 31±6 and 30±6 mm,
P
=0.0005; length, 66±7 versus 61±7 and 61±7 mm,
P
<0.0001), more right ventricular dysfunction, increased epicardial fat thickness (10±2 versus 7±2 and 6±2 mm;
P
<0.0001), and greater total epicardial heart volume (945 mL [831–1105 mL] versus 797 mL [643–979 mL] and 632 mL [517–768 mL];
P
<0.0001), despite lower N-terminal pro-B-type natriuretic peptide levels. Pulmonary capillary wedge pressure was correlated with body mass and plasma volume in obese HFpEF (
r
=0.22 and 0.27, both
P
<0.05) but not in nonobese HFpEF (
P
≥0.3). The increase in heart volumes in obese HFpEF was associated with greater pericardial restraint and heightened ventricular interdependence, reflected by increased ratio of right- to left-sided heart filling pressures (0.64±0.17 versus 0.56±0.19 and 0.53±0.20;
P
=0.0004), higher pulmonary venous pressure relative to left ventricular transmural pressure, and greater left ventricular eccentricity index (1.10±0.19 versus 0.99±0.06 and 0.97±0.12;
P
<0.0001). Interdependence was enhanced as pulmonary artery pressure load increased (
P
for interaction <0.05). Compared with those with nonobese HFpEF and control subjects, obese patients with HFpEF displayed worse exercise capacity (peak oxygen consumption, 7.7±2.3 versus 10.0±3.4 and12.9±4.0 mL/min·kg;
P
<0.0001), higher biventricular filling pressures with exercise, and depressed pulmonary artery vasodilator reserve.

Conclusions:
Obesity-related HFpEF is a genuine form of cardiac failure and a clinically relevant phenotype that may require specific treatments.
Associations of Blood Pressure Dipping Patterns With Left Ventricular Mass and Left Ventricular Hypertrophy in Blacks: The Jackson Heart Study
Authors: Abdalla Marwah , Caughey Melissa C. , Tanner Rikki M. , Booth John N. , Diaz Keith M. , Anstey D. Edmund , Sims Mario , Ravenell Joseph , Muntner Paul , Viera Anthony J. , Shimbo Daichi 
Published: April 2017

Background

Abnormal diurnal blood pressure (
BP
), including nondipping patterns, assessed using ambulatory
BP
monitoring, have been associated with increased cardiovascular risk among white and Asian adults. We examined the associations of
BP
dipping patterns (dipping, nondipping, and reverse dipping) with cardiovascular target organ damage (left ventricular mass index and left ventricular hypertrophy), among participants from the Jackson Heart Study, an exclusively black population–based cohort.

Methods and Results

Analyses included 1015 participants who completed ambulatory
BP
monitoring and had echocardiography data from the baseline visit. Participants were categorized based on the nighttime to daytime systolic
BP
ratio into 3 patterns: dipping pattern (≤0.90), nondipping pattern (>0.90 to ≤1.00), and reverse dipping pattern (>1.00). The prevalence of dipping, nondipping, and reverse dipping patterns was 33.6%, 48.2%, and 18.2%, respectively. In a fully adjusted model, which included antihypertensive medication use and clinic and daytime systolic
BP
, the mean differences in left ventricular mass index between reverse dipping pattern versus dipping pattern was 8.3±2.1 g/m
2
(
P
<0.001) and between nondipping pattern versus dipping pattern was −1.0±1.6 g/m
2
(
P
=0.536). Compared with participants with a dipping pattern, the prevalence ratio for having left ventricular hypertrophy was 1.65 (95% CI, 1.05–2.58) and 0.96 (95% CI, 0.63–1.97) for those with a reverse dipping pattern and nondipping pattern, respectively.

Conclusions

In this population‐based study of blacks, a reverse dipping pattern was associated with increased left ventricular mass index and a higher prevalence of left ventricular hypertrophy. Identification of a reverse dipping pattern on ambulatory
BP
monitoring may help identify black at increased risk for cardiovascular target organ damage.