bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reflex bronchoconstriction evoked by inhaled nicotine aerosol in guinea pigs: role of the nicotinic acetylcholine receptor
Authors: Lee L.-Y. , Lin R.-L. , Khosravi M. , Xu F. 
Published: January 2018

Inhaled cigarette smoke stimulated vagal bronchopulmonary C fibers via an action of nicotine on neuronal nicotinic acetylcholine receptor (nAChR). Recent studies have reported that nicotine at high concentrations can also activate the transient receptor potential ankyrin 1 receptor (TRPA1) expressed in these sensory nerves. This study was performed to characterize the airway response to inhaled nicotine aerosol and to investigate the relative roles of nAChR and TRPA1 in this response. Guinea pigs were anesthetized and mechanically ventilated; one tidal volume of nicotine aerosol (2% solution) was diluted by an equal volume of air and delivered directly into the lung via a tracheal cannula in a single breath. Our results showed the following: 1) Inhalation of nicotine aerosol triggered an immediate and pronounced bronchoconstriction; the increase in total pulmonary resistance reached a peak of 588 ± 205% (mean ± SE) in 10–40 s, which gradually returned to baseline after 1–5 min. 2) Pretreatment with either atropine (iv) or mecamylamine (aerosol) almost completely abolished the nicotine-induced bronchoconstriction; the mecamylamine pretreatment did not block the bronchoconstriction and bradycardia evoked by electrical stimulation of the distal end of one sectioned vagus nerve, indicating its minimal systemic effects. 3) Pretreatment with HC-030031, a selective TRPA1 antagonist, abolished the bronchoconstriction induced by allyl isothiocyanate, a selective TRPA1 agonist, but did not attenuate the nicotine-evoked bronchoconstriction. In conclusion, inhalation of a single breath of nicotine aerosol evoked acute bronchoconstriction mediated through the cholinergic reflex pathway. This reflex response was triggered by activation of nAChR, but not TRPA1, located in airway sensory nerves. NEW & NOTEWORTHY Recent reports revealed that nicotine at high concentration activated transient receptor potential ankyrin 1 receptor (TRPA1) expressed in vagal bronchopulmonary sensory nerves. This study showed that inhalation of a single breath of nicotine aerosol consistently evoked acute bronchoconstriction that was mediated through the cholinergic reflex pathway and triggered by activation of nicotinic acetylcholine receptor, but not TRPA1, located in these nerves. This is new and important information considering the recent rapid and alarming rise in the prevalence of e-cigarette use for nicotine inhalation.
The Novel Oncolytic Adenoviral Mutant Ad5-3Δ-A20T Retargeted to αvβ6 Integrins Efficiently Eliminates Pancreatic Cancer Cells
Authors: Man Y. K. Stella , Davies James A. , Coughlan Lynda , Pantelidou Constantia , Blázquez-Moreno Alfonso , Marshall John F. , Parker Alan L. , Halldén Gunnel 
Published: January 2018

Abstract
Metastatic pancreatic ductal adenocarcinomas (PDAC) are incurable due to the rapid development of resistance to all current therapeutics. Oncolytic adenoviral mutants have emerged as a promising new strategy that negates such resistance. In contrast to normal tissue, the majority of PDACs express the αvβ6 integrin receptor. To exploit this feature, we modified our previously reported oncolytic adenovirus, AdΔΔ, to selectively target αvβ6 integrins to facilitate systemic delivery. Structural modifications to AdΔΔ include the expression of the small but potent αvβ6-binding peptide, A20FMDV2, and ablation of binding to the native coxsackie and adenovirus receptor (CAR) within the fiber knob region. The resultant mutant, Ad5-3Δ-A20T, infected and killed αvβ6 integrin–expressing cells more effectively than the parental wild-type (Ad5wt) virus and AdΔΔ. Viral uptake through αvβ6 integrins rather than native viral receptors (CAR, αvβ3 and αvβ5 integrins) promoted viral propagation and spread. Superior efficacy of Ad5-3Δ-A20T compared with Ad5wt was demonstrated in 3D organotypic cocultures, and similar potency between the two viruses was observed in Suit-2 in vivo models. Importantly, Ad5-3Δ-A20T infected pancreatic stellate cells at low levels, which may further facilitate viral spread and cancer cell elimination either as a single agent or in combination with the chemotherapy drug, gemcitabine. We demonstrate that Ad5-3Δ-A20T is highly selective for αvβ6 integrin–expressing pancreatic cancer cells, and with further development, this new and exciting strategy can potentially be extended to improve the systemic delivery of adenoviruses to pancreatic cancer patients. Mol Cancer Ther; 17(2); 575–87. ©2018 AACR.
Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer
Authors: Annala Matti , Vandekerkhove Gillian , Khalaf Daniel , Taavitsainen Sinja , Beja Kevin , Warner Evan W. , Sunderland Katherine , Kollmannsberger Christian , Eigl Bernhard J. , Finch Daygen , Oja Conrad D. , Vergidis Joanna , Zulfiqar Muhammad , Azad Arun A. , Nykter Matti , Gleave Martin E. , Wyatt Alexander W. , Chi Kim N. 
Published: January 2018

Abstract
Primary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers.
Significance: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 444–57. ©2018 AACR.
See related commentary by Jayaram et al., p. 392.
This article is highlighted in the In This Issue feature, p. 371
Plasminogen Activator Inhibitor-1 Promotes Neutrophil Infiltration and Tissue Injury on Ischemia–Reperfusion
Authors: Praetner Marc , Zuchtriegel Gabriele , Holzer Martin , Uhl Bernd , Schaubächer Johanna , Mittmann Laura , Fabritius Matthias , Fürst Robert , Zahler Stefan , Funken Dominik , Lerchenberger Maximilian , Khandoga Andrej , Kanse Sandip , Lauber Kirsten , Krombach Fritz , Reichel Christoph A. 
Published: January 2018

Objective—
Ischemia–reperfusion (I/R) injury significantly contributes to organ dysfunction and failure after myocardial infarction, stroke, and transplantation. In addition to its established role in the fibrinolytic system, plasminogen activator inhibitor-1 has recently been implicated in the pathogenesis of I/R injury. The underlying mechanisms remain largely obscure.

Approach and Results—
Using different in vivo microscopy techniques as well as ex vivo analyses and in vitro assays, we identified that plasminogen activator inhibitor-1 rapidly accumulates on microvascular endothelial cells on I/R enabling this protease inhibitor to exhibit previously unrecognized functional properties by inducing an increase in the affinity of β2 integrins in intravascularly rolling neutrophils. These events are mediated through low-density lipoprotein receptor–related protein-1 and mitogen-activated protein kinase–dependent signaling pathways that initiate intravascular adherence of these immune cells to the microvascular endothelium. Subsequent to this process, extravasating neutrophils disrupt endothelial junctions and promote the postischemic microvascular leakage. Conversely, deficiency of plasminogen activator inhibitor-1 effectively reversed leukocyte infiltration, microvascular dysfunction, and tissue injury on experimental I/R without exhibiting side effects on microvascular hemostasis.

Conclusions—
Our experimental data provide novel insights into the nonfibrinolytic properties of the fibrinolytic system and emphasize plasminogen activator inhibitor-1 as a promising target for the prevention and treatment of I/R injury.
Hyporesponsiveness to Darbepoetin Alfa in Patients With Heart Failure and Anemia in the RED-HF Study (Reduction of Events by Darbepoetin Alfa in Heart Failure)
Authors: van der Meer Peter , Grote Beverborg Niels , Pfeffer Marc A. , Olson Kurt , Anand Inder S. , Westenbrink B. Daan , McMurray John J.V. , Swedberg Karl , Young James B. , Solomon Scott D. , van Veldhuisen Dirk J. 
Published: January 2018

Background:
A poor response to erythropoiesis-stimulating agents such as darbepoetin alfa has been associated with adverse outcomes in patients with diabetes mellitus, chronic kidney disease, and anemia; whether this is also true in heart failure is unclear.

Methods and Results:
We performed a post hoc analysis of the RED-HF trial (Reduction of Events by Darbepoetin Alfa in Heart Failure), in which 1008 patients with systolic heart failure and anemia (hemoglobin level, 9.0–12.0 g/dL) were randomized to darbepoetin alfa. We examined the relationship between the hematopoietic response to darbepoetin alfa and the incidence of all-cause death or first heart failure hospitalization during a follow-up of 28 months. For the purposes of the present study, patients in the lowest quartile of hemoglobin change after 4 weeks were considered nonresponders. The median initial hemoglobin change in nonresponders (n=252) was −0.25 g/dL and +1.00 g/dL in the remainder of patients (n=756). Worse renal function, lower sodium levels, and less use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were independently associated with nonresponse. Although a low endogenous erythropoietin level helped to differentiate responders from nonresponders, its predictive value in a multivariable model was poor (C statistic=0.69). Nonresponders had a higher rate of all-cause death or first heart failure hospitalization (hazard ratio, 1.25; 95% confidence interval, 1.02–1.54) and a higher risk of all-cause mortality (hazard ratio, 1.30; 95% confidence interval, 1.04–1.63) than responders.

Conclusions:
A poor response to darbepoetin alfa was associated with worse outcomes in heart failure patients with anemia. Patients with a poor response were difficult to identify using clinical and biochemical biomarkers.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00358215.
Targeting Chondroitin Sulfate Glycosaminoglycans to Treat Cardiac Fibrosis in Pathological Remodeling
Authors: Zhao Rong-Rong , Ackers-Johnson Matthew , Stenzig Justus , Chen Chen , Ding Tao , Zhou Yue , Wang Peipei , Ng Shi Ling , Li Peter Y. , Teo Gavin , Rudd Pauline M. , Fawcett James W. , Foo Roger S.Y. 
Published: January 2018

Background:
Heart failure is a leading cause of mortality and morbidity, and the search for novel therapeutic approaches continues. In the monogenic disease mucopolysaccharidosis VI, loss-of-function mutations in arylsulfatase B lead to myocardial accumulation of chondroitin sulfate (CS) glycosaminoglycans, manifesting as myriad cardiac symptoms. Here, we studied changes in myocardial CS in nonmucopolysaccharidosis failing hearts and assessed its generic role in pathological cardiac remodeling.

Methods:
Healthy and diseased human and rat left ventricles were subjected to histological and immunostaining methods to analyze glycosaminoglycan distribution. Glycosaminoglycans were extracted and analyzed for quantitative and compositional changes with Alcian blue assay and liquid chromatography–mass spectrometry. Expression changes in 20 CS-related genes were studied in 3 primary human cardiac cell types and THP-1–derived macrophages under each of 9 in vitro stimulatory conditions. In 2 rat models of pathological remodeling induced by transverse aortic constriction or isoprenaline infusion, recombinant human arylsulfatase B (rhASB), clinically used as enzyme replacement therapy in mucopolysaccharidosis VI, was administered intravenously for 7 or 5 weeks, respectively. Cardiac function, myocardial fibrosis, and inflammation were assessed by echocardiography and histology. CS-interacting molecules were assessed with surface plasmon resonance, and a mechanism of action was verified in vitro.

Results:
Failing human hearts displayed significant perivascular and interstitial CS accumulation, particularly in regions of intense fibrosis. Relative composition of CS disaccharides remained unchanged. Transforming growth factor–β induced CS upregulation in cardiac fibroblasts. CS accumulation was also observed in both the pressure-overload and the isoprenaline models of pathological remodeling in rats. Early treatment with rhASB in the transverse aortic constriction model and delayed treatment in the isoprenaline model proved rhASB to be effective at preventing cardiac deterioration and augmenting functional recovery. Functional improvement was accompanied by reduced myocardial inflammation and overall fibrosis. Tumor necrosis factor–α was identified as a direct binding partner of CS glycosaminoglycan chains, and rhASB reduced tumor necrosis factor–α—induced inflammatory gene activation in vitro in endothelial cells and macrophages.

Conclusions:
CS glycosaminoglycans accumulate during cardiac pathological remodeling and mediate myocardial inflammation and fibrosis. rhASB targets CS effectively as a novel therapeutic approach for the treatment of heart failure.
Recombinant Human ADAMTS13 Treatment Improves Myocardial Remodeling and Functionality After Pressure Overload Injury in Mice
Authors: Witsch Thilo , Martinod Kimberly , Sorvillo Nicoletta , Portier Irina , De Meyer Simon F. , Wagner Denisa D. 
Published: January 2018

Background
A disintegrin‐like metalloproteinase with thrombospondin motif type 1 member 13 (ADAMTS13), the von Willebrand factor–cleaving enzyme, decreases leukocyte and platelet recruitment and, thus, reduces thrombosis and inflammation. Recombinant human ADAMTS13 (rhADAMTS13) is a novel drug candidate for ischemia/reperfusion injury and has shown short‐term benefits in mouse models of myocardial injury, but long‐term outcome has not been investigated.

Methods and Results
We evaluated the impact of rhADAMTS13 on cardiac remodeling, scarring, and contractile function, under chronic left ventricular pressure overload. The role of von Willebrand factor and the effect of rhADAMTS13 treatment were studied. This model of heart failure, based on ascending aortic constriction, produces a coronary inflammatory response and microvascular dysfunction, resulting in fibrotic remodeling and cardiac failure. Mice were treated with either rhADAMTS13 or vehicle and assessed for coronary vascular inflammation and ventricular function at several postsurgical time points, as well as for cardiac fibrosis after 4 weeks. Early upon induction of pressure overload under rhADAMTS13 treatment, we detected less endothelial‐lumen–associated von Willebrand factor, fewer platelet aggregates, and decreased activated transforming growth factor‐β1 levels than in vehicle‐treated mice. We observed significant preservation of cardiac function and decrease in fibrotic remodeling as a result of rhADAMTS13 administration.

Conclusions
Herein, we show that rhADAMTS13 decreases coronary vascular dysfunction and improves cardiac remodeling after left ventricular pressure overload in mice. We propose that this effect may, at least in part, be the result of decreased von Willebrand factor–mediated recruitment of platelets, a major source of the activated profibrotic cytokine transforming growth factor‐β1. Our study further supports the therapeutic potential of rhADAMTS13 for conditions characterized by inflammatory cardiac damage that results in fibrosis.
Vagus Nerve Stimulation Enhances Stable Plasticity and Generalization of Stroke Recovery
Authors: Meyers Eric C. , Solorzano Bleyda R. , James Justin , Ganzer Patrick D. , Lai Elaine S. , Rennaker Robert L. , Kilgard Michael P. , Hays Seth A. 
Published: January 2018

Background and Purpose—
Chronic impairment of the arm and hand is a common consequence of stroke. Animal and human studies indicate that brief bursts of vagus nerve stimulation (VNS) in conjunction with rehabilitative training improve recovery of motor function after stroke. In this study, we tested whether VNS could promote generalization, long-lasting recovery, and structural plasticity in motor networks.

Methods—
Rats were trained on a fully automated, quantitative task that measures forelimb supination. On task proficiency, unilateral cortical and subcortical ischemic lesions were administered. One week after ischemic lesion, rats were randomly assigned to receive 6 weeks of rehabilitative training on the supination task with or without VNS. Rats then underwent 4 weeks of testing on a task assessing forelimb strength to test generalization of recovery. Finally, the durability of VNS benefits was tested on the supination task 2 months after the cessation of VNS. After the conclusion of behavioral testing, viral tracing was performed to assess synaptic connectivity in motor networks.

Results—
VNS enhances plasticity in corticospinal motor networks to increase synaptic connectivity to musculature of the rehabilitated forelimb. Adding VNS more than doubled the benefit of rehabilitative training, and the improvements lasted months after the end of VNS. Pairing VNS with supination training also significantly improved performance on a similar, but untrained task that emphasized volitional forelimb strength, suggesting generalization of forelimb recovery.

Conclusions—
This study provides the first evidence that VNS paired with rehabilitative training after stroke (1) doubles long-lasting recovery on a complex task involving forelimb supination, (2) doubles recovery on a simple motor task that was not paired with VNS, and (3) enhances structural plasticity in motor networks.
Size of Ruptured Intracranial Aneurysms Is Decreasing
Authors: Korja Miikka , Kivisaari Riku , Rezai Jahromi Behnam , Lehto Hanna 
Published: January 2018

Background and Purpose—
Decrease in the incidence of subarachnoid hemorrhage over the past decades has been related to decreased smoking rates, especially among <50-year-old people. We studied whether these epidemiological changes are reflected in changes in the size and location of ruptured intracranial aneurysms (RIAs).

Methods—

We identified consecutive patients admitted to a nonprofit academic hospital with saccular RIAs between 1989 and 2008. We averaged and analyzed mean sizes of RIAs in 4-year admission groups. In statistical analysis, we used the χ
2
test for categorical variables and the Kruskal–Wallis test to assess differences between continuous and categorical variables. For linear trend assessments, we used the linear-by-linear association and ANOVA tests.

Results—

Of 2660 consecutive patients (59% women) with RIAs, 1176 (44%) were <50 years on admission. In people <50 years, the averaged annual mean size of RIAs decreased 16% from 9.2 mm in 1989 to 1992 to 7.7 mm in 2005 to 2008 in women and 13% (from 9.3 to 8.1 mm) in men (decreasing linear trend;
P
=0.001). RIA sizes did not change in 50-year-old or older patients, whereas the proportion of posterior circulation RIAs almost tripled to 13%, also with a linear relationship (
P
<0.001).

Conclusions—
The size of RIAs seems to be decreasing among younger generations of hospital-admitted subarachnoid hemorrhage patients, whereas 50-year-old and older subarachnoid hemorrhage patients have an increasing proportion of posterior circulation RIAs. These epidemiological changes are noteworthy, especially if they are universal and ongoing.
Pharmacy Student Monitoring of Direct Oral Anticoagulants
Authors: Kim Jennifer J. , Hill Hailey L. , Groce James B. , Granfortuna James M. , Makhlouf Tanya K. 
Published: January 2018

Background: Best practice recommendations are lacking. Thus far, literature has described pharmacist-led DOAC monitoring. Objective: The purpose of this study is to describe a DOAC monitoring program involving pharmacy students. Methods: This was an observational analysis of a quality improvement initiative. A clinical pharmacist preceptor identified clinic patients taking DOACs by running a report using the electronic medical record. Pharmacy students conducted chart reviews, called pharmacies for 6-month refill histories, and interviewed and educated patients. Findings were communicated to the care team and interventions were performed as applicable with the preceptor. Results: Of 90 patients included, the mean age was 63 years, 54% were female, and 65.6% were black or African American. Rivaroxaban and apixaban were used most commonly. Sixty-two percent of DOACs were prescribed for atrial fibrillation/flutter, while 32.2% for venous thromboembolism. The mean MPR was 77.1%, with 27.7% of patients having an MPR ≤60%. Of the 136 student-led interventions, 25.2% involved medication access, 24.4% adherence education, 20.7% processing refills, 14.8% laboratory monitoring recommendations, 8.9% switching or recommending switching to another anticoagulant, and 4.4% stopping a nonsteroidal anti-inflammatory drug or aspirin. Conclusion: Pharmacy students can help to ensure medication safety and effective use of DOACs.
Use of 3D Prints to Compare the Efficacy of Three Different Calcaneal Osteotomies for the Correction of Heel Varus
Authors: Pfeffer Glenn B. , Michalski Max P. , Basak Tina , Giaconi Joseph C. 
Published: January 2018

Background: Cavovarus deformity of the hindfoot is typically caused by neurologic disorders. Multiple osteotomies have been described for the correction of varus deformity but without clinical comparison. In this study, we used 18 identical 3-dimensional (3D) prints of a patient with heel varus to compare the operative correction obtained with Dwyer, oblique, and Z osteotomies. Methods: A computed tomography (CT) scan of a patient with heel varus was used to create 18 identical 3D prints of the talus, calcaneus, and cuboid. Coordinate frames were added to the talus and calcaneus to evaluate rotation. The prints were then divided into 3 groups of 6 models each. A custom jig precisely and accurately replicated each osteotomy. Following the simulated operations, cut models were CT scanned and compared with 6 uncut models. Measurements were calculated using multiplanar reconstruction image processing. An analysis of variance (ANOVA) was performed on the initial data to determine significant differences among the measured variables. A Tukey Studentized range test was run to compare variables that showed statistically significant differences using the ANOVA. Results: The coronal angle of the Dwyer and oblique osteotomies was significantly less than that of the Z osteotomy ( P < .05). The axial angle, lateral displacement, and calcaneal shortening of the uncut model and Z osteotomy were significantly less than the Dwyer and oblique osteotomies. Conclusions: Dwyer, oblique, and Z osteotomies did not create either lateral translation or coronal rotation without the addition of a lateralizing slide or rotation of the posterior tuberosity. Clinical Relevance: Dwyer and oblique osteotomies would be best suited for mild deformity, yet the amount of calcaneal shortening must be acknowledged. A Z osteotomy is a complex procedure that has the capability of correcting moderate-severe coronal plane rotation but fails to provide lateralization of the pull of the Achilles insertion.