bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of real-time visual feedback device ‘Quality Cardiopulmonary Resuscitation (QCPR) Classroom’ with a metronome sound on layperson CPR training in Japan: a cluster randomized control trial
Authors: Tanaka Shota , Tsukigase Kyoko , Hara Takahiro , Sagisaka Ryo , Myklebust Helge , Birkenes Tonje Soraas , Takahashi Hiroyuki , Iwata Ayana , Kidokoro Yutaro , Yamada Momoyo , Ueta Hiroki , Takyu Hiroshi , Tanaka Hideharu 
Published: June 2019

Objectives‘Quality Cardiopulmonary Resuscitation (QCPR) Classroom’ was recently introduced to provide higher-quality Cardiopulmonary Resuscitation (CPR) training. This study aimed to examine whether novel QCPR Classroom training can lead to higher chest-compression quality than standard CPR training.DesignA cluster randomised controlled trial was conducted to compare standard CPR training (control) and QCPR Classroom (intervention).SettingLayperson CPR training in Japan.ParticipantsSix hundred forty-two people aged over 15 years were recruited from among CPR trainees.InterventionsCPR performance data were registered without feedback on instrumented Little Anne prototypes for 1 min pretraining and post-training. A large classroom was used in which QCPR Classroom participants could see their CPR performance on a big screen at the front; the control group only received instructor’s subjective feedback.Primary and secondary outcome measuresThe primary outcomes were compression depth (mm), rate (compressions per minute (cpm)), percentage of adequate depth (%) and recoil (%). Survey scores were a secondary outcome. The survey included participants’ confidence regarding CPR parameters and ease of understanding instructor feedback.ResultsIn total, 259 and 238 people in the control and QCPR Classroom groups, respectively, were eligible for analysis. After training, the mean compression depth and rate were 56.1±9.8 mm and 119.2±7.3 cpm in the control group and 59.5±7.9 mm and 116.8±5.5 cpm in the QCPR Classroom group. The QCPR Classroom group showed significantly more adequate depth than the control group (p=0.001). There were 39.0% (95% CI 33.8 to 44.2; p<0.0001) and 20.0% improvements (95% CI 15.4 to 24.7; P<0.0001) in the QCPR Classroom and control groups, respectively. The difference in adequate recoil between pretraining and post-training was 2.7% (95% CI −1.7 to 7.1; pre 64.2±36.5% vs post 66.9%±34.6%; p=0.23) and 22.6% in the control and QCPR Classroom groups (95% CI 17.8 to 27.3; pre 64.8±37.5% vs post 87.4%±22.9%; p<0.0001), respectively.ConclusionsQCPR Classroom helped students achieve high-quality CPR training, especially for proper compression depth and full recoil. For good educational achievement, a novel QCPR Classroom with a metronome sound is recommended.
Deletion of Calcineurin Promotes a Protumorigenic Fibroblast Phenotype
Authors: Lieberman Allyson , Barrett Richard , Kim Jaewon , Zhang Kathy L. , Avery Diana , Monslow James , Kim Hyunsoo , Kim Bang-Jin , Puré Ellen , Ryeom Sandra 
Published: June 2019

Abstract

Fibroblast activation is a crucial step in tumor growth and metastatic progression. Activated fibroblasts remodel the extracellular matrix (ECM) in primary tumor and metastatic microenvironments, exerting both pro- and antitumorigenic effects. However, the intrinsic mechanisms that regulate the activation of fibroblasts are not well-defined. The signaling axis comprising the calcium-activated Ser/Thr phosphatase calcineurin (CN), and its downstream target nuclear factor of activated T cells, has been implicated in endothelial (EC) and immune cell activation, but its role in fibroblasts is not known. Here, we demonstrate that deletion of CN in fibroblasts in vitro altered fibroblast morphology and function consistent with an activated phenotype relative to wild-type fibroblasts. CN-null fibroblasts had a greater migratory capacity, increased collagen secretion and remodeling, and promoted more robust EC activation in vitro. ECM generated by CN-null fibroblasts contained more collagen with greater alignment of fibrillar collagen compared with wild-type fibroblast-derived matrix. These differences in matrix composition and organization imposed distinct changes in morphology and cytoskeletal architecture of both fibroblasts and tumor cells. Consistent with this in vitro phenotype, mice with stromal CN deletion had a greater incidence and larger lung metastases. Our data suggest that CN signaling contributes to the maintenance of fibroblast homeostasis and that loss of CN is sufficient to promote fibroblast activation.

Significance:
Calcineurin signaling is a key pathway underlying fibroblast homeostasis that could be targeted to potentially prevent fibroblast activation in distant metastatic sites.
High-Plex Predictive Marker Discovery for Melanoma Immunotherapy–Treated Patients Using Digital Spatial Profiling
Authors: Toki Maria I. , Merritt Christopher R. , Wong Pok Fai , Smithy James W. , Kluger Harriet M. , Syrigos Konstantinos N. , Ong Giang T. , Warren Sarah E. , Beechem Joseph M. , Rimm David L. 
Published: June 2019

Abstract

Purpose:
Protein expression in formalin-fixed, paraffin-embedded tissue is routinely measured by IHC or quantitative fluorescence (QIF) on a handful of markers on a single section. Digital spatial profiling (DSP) allows spatially informed simultaneous assessment of multiple biomarkers. Here we demonstrate the DSP technology using a 44-plex antibody cocktail to find protein expression that could potentially be used to predict response to immune therapy in melanoma.
Experimental Design: The NanoString GeoMx DSP technology is compared with automated QIF (AQUA) for immune marker compartment-specific measurement and prognostic value in non–small cell lung cancer (NSCLC). Then we use this tool to search for novel predictive markers in a cohort of 60 patients with immunotherapy-treated melanoma on a tissue microarray using a 44-plex immune marker panel measured in three compartments (macrophage, leukocyte, and melanocyte) generating 132 quantitative variables.

Results:
The spatially informed variable assessment by DSP validates by both regression and variable prognostication compared with QIF for stromal CD3, CD4, CD8, CD20, and PD-L1 in NSCLC. From the 132 variables, 11 and 15 immune markers were associated with prolonged progression-free survival (PFS) and overall survival (OS). Notably, we find PD-L1 expression in CD68-positive cells (macrophages) and not in tumor cells was a predictive marker for PFS, OS, and response.

Conclusions:
DSP technology shows high concordance with QIF and validates based on both regression and outcome assessment. Using the high-plex capacity, we found a series of expression patterns associated with outcome, including that the expression of PD-L1 in macrophages is associated with response.
Aggressive Progression in Glioblastoma Cells through Potentiated Activation of Integrin α5β1 by the Tenascin-C–Derived Peptide TNIIIA2
Authors: Fujita Motomichi , Yamamoto Tetsuya , Iyoda Takuya , Fujisawa Tatsuya , Sasada Manabu , Nagai Reo , Kudo Chikako , Otsuka Kazuki , Kamiya Sadahiro , Kodama Hiroaki , Fukai Fumio 
Published: June 2019

Abstract

Tenascin-C is a member of the matricellular protein family, and its expression level is correlated to poor prognosis in cancer, including glioblastoma, whereas its substantial role in tumor formation and malignant progression remains controversial. We reported previously that peptide TNIIIA2 derived from the cancer-associated alternative splicing domain of tenascin-C molecule has an ability to activate β1-integrin strongly and to maintain it for a long time. Here, we demonstrate that β1-integrin activation by TNIIIA2 causes acquisition of aggressive behavior, dysregulated proliferation, and migration, characteristic of glioblastoma cells. TNIIIA2 hyperstimulated the platelet-derived growth factor–dependent cell survival and proliferation in an anchorage-independent as well as -dependent manner in glioblastoma cells. TNIIIA2 also strongly promoted glioblastoma multiforme cell migration, which was accompanied by an epithelial–mesenchymal transition–like morphologic change on the fibronectin substrate. Notably, acquisition of these aggressive properties by TNIIIA2 in glioblastoma cells was abrogated by peptide FNIII14 that is capable of inducing inactivation in β1-integrin activation. Moreover, FNIII14 significantly inhibited tumor growth in a mouse xenograft glioblastoma model. More importantly, FNIII14 sensitized glioblastoma cells to temozolomide via downregulation of O6-methylguanine-DNA methyltransferase expression. Consequently, FNIII14 augmented the antitumor activity of temozolomide in a mouse xenograft glioblastoma model. Taken altogether, the present study provides not only an interpretation for the critical role of tenascin-C/TNIIIA2 in aggressive behavior of glioblastoma cells, but also an important strategy for glioblastoma chemotherapy. Inhibition of the tenascin-C/β1-integrin axis may be a therapeutic target for glioblastoma, and peptide FNIII14 may represent a new approach for glioblastoma chemotherapy.

Significance:
These findings provide a proposal of new strategy for glioblastoma chemotherapy based on integrin inactivation.
Therapeutic Effect of Y-27632 on Tumorigenesis and Cisplatin-Induced Peripheral Sensory Loss through RhoA–NF-κB
Authors: Zhu Yi , Howard George A. , Pittman Keith , Boykin Christi , Herring Laura E. , Wilkerson Emily M. , Verbanac Kathryn , Lu Qun 
Published: June 2019

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer therapy that frequently requires a reduction or cessation of treatments and negatively impacts the patient's quality of life. There is currently no effective means to prevent or treat CIPN. In this study, we developed and applied CIPN in an immunocompetent, syngeneic murine Lewis Lung Carcinoma (LLCab) model that enabled the elucidation of both tumor and host responses to cisplatin and treatments of Y-27632, a selective inhibitor of Rho kinase/p160ROCK. Y-27632 not only preserved cisplatin's efficacy toward tumor suppression but also the combination treatment inhibited tumor cell proliferation and increased cellular apoptosis. By alleviating the cisplatin-induced loss of epidermal nerve fibers (ENFs), Y-27632 protected tumor-bearing mice from cisplatin-induced reduction of touch sensation. Furthermore, quantitative proteomic analysis revealed the striking cisplatin-induced dysregulation in cellular stress (inflammation, mitochondrial deficiency, DNA repair, etc.)–associated proteins. Y-27632 was able to reverse the changes of these proteins that are associated with Rho GTPase and NF-κB signaling network, and also decreased cisplatin-induced NF-κB hyperactivation in both footpad tissues and tumor. Therefore, Y-27632 is an effective adjuvant in tumor suppression and peripheral neuroprotection. These studies highlight the potential of targeting the RhoA–NF-κB axis as a combination therapy to treat CIPN.

Implications:
This study, for the first time, demonstrated the dual antineoplastic and neuroprotective effects of Rho kinase/p160ROCK inhibition in a syngeneic immunocompetent tumor-bearing mouse model, opening the door for further clinical adjuvant development of RhoA–NF-κB axis to improve chemotherapeutic outcomes.
Identification of De Novo Enhancers Activated by TGFβ to Drive Expression of CDKN2A and B in HeLa Cells
Authors: Liu Yen-Ting , Xu Lin , Bennett Lynda , Hooks Jared C. , Liu Jing , Zhou Qinbo , Liem Priscilla , Zheng Yanbin , Skapek Stephen X. 
Published: June 2019

Abstract

Disruption of the CDKN2A (INK4A/ARF) and B (INK4B) genes, which encode three function-independent tumor suppressors, is one of the most common events in human cancer. Because their relative importance in tumor prevention appears to be species- and context-specific, studying their regulation can shed light on mechanisms by which they are bypassed in malignant transformation. We previously unveiled a new pathway in which TGFβ selectively induces Arf at mouse Cdkn2a in eye development and cultured fibroblasts. As TGFβ signaling is often derailed in cancer development or progression, we investigated its control of CDKN2A/B in human cancer. Computational analyses of sequencing and array data from nearly 11,000 patients with cancer in TCGA showed discordant expression of ARF and INK4A in most cancer subtypes, with gene copy-number loss and promoter methylation involved in only a subset. Using HeLa cells as a model, we found that exogenous TGFβ induced ARF mRNA and protein, and ARF knockdown limited TGFβ-mediated growth suppression. TGFβ-mediated ARF mRNA induction required SMAD2/3, p38MAPK, and SP1, and ARF mRNA was induced without added RNAPII recruitment. Chromatin immunoprecipitation unveiled a remote enhancer element engaged by TGFβ by a mechanism that partially depended on p38MAPK. CRISPR-based editing of this enhancer limited induction of ARF and INK4B by TGFβ, but not by oncogenic RAS.

Implications:
Our findings reveal new molecular mechanisms by which CDKN2A/B regulation is coupled to external cues, and those findings represent entry points to further explore pharmacologic strategies to restore their expression in cancer.
Long-Term Effect of Different Optimizing Methods for Cardiac Resynchronization Therapy in Patients with Heart Failure: A Randomized and Controlled Pilot Study
Authors: Zhang Yu  , Xing Qiang  , Zhang Jiang-Hua , Jiang Wei-Feng  , Qin Mu  , Liu Xu  
Published: June 2019

<b><i>Aim:</i></b> During cardiac resynchronization therapy (CRT), optimized programming of the atrioventricular (AV) delay and ventricular-to-ventricular (VV) interval can lead to improved hemodynamics, symptomatic response, and left ventricular systolic function. Currently, however, there is no recommendation for the best optimization method. This study aimed to compare the long-term clinical outcomes of 4 different CRT optimization methods. <b><i>Methods:</i></b> One hundred and twenty-four consecutive CRT patients with severe heart failure and left bundle-branch block configuration were randomly assigned into four groups to undergo AV/VV delay optimization through echocardiogram (ECHO; <i>n</i> = 30), electrocardiogram (ECG; <i>n</i> = 32), QuickOpt algorithm (<i>n</i> = 28), and nominal AV/VV (<i>n</i> = 36) groups. Patients were followed up and underwent examinations, including New York Heart Association (NYHA) cardiac functional classification, 6-min walking distance (6MWD), and echocardiography, at 6, 12, 24, 36, and 48 months, respectively. The patients’ survival and clinical outcomes were compared among the four groups. <b><i>Results:</i></b> Kaplan-Meier survival analyses showed that the median survival was the same in the 4 groups: ECHO, 43 months; ECG, 44 months; QuickOpt, 44 months, and nominal, 41 months. At the 6-month follow-up, the reduction in left ventricular end diastolic diameter (LVEDD) was significantly less in the nominal group (–1.91 ± 2.58 mm) than that in the other three groups (ECHO: –3.70 ± 2.78 mm, <i>p</i> = 0.012; ECG: –3.53 ± 3.14 mm, <i>p</i> = 0.020; QuickOpt: –3.46 ± 2.65 mm, <i>p</i> = 0.032); 6MWD was significantly shorter in the nominal group (87.88 ± 34.76 m) than that in the other three groups (ECHO: 120.63 ± 56.93 m, <i>p</i> = 0.006; ECG: 114.97 ± 54.95 m, <i>p</i> = 0.020; QuickOpt: 114.57 ± 35.41 m, <i>p</i> = 0.027). Left ventricular ejection fraction (LVEF) significantly increased in ECHO (7.23 ± 2.76%, <i>p</i> = 0.010), ECG (8.50 ± 3.17%, <i>p</i> &#x3c; 0.001), and QuickOpt (8.39 ± 2.90%, <i>p</i> &#x3c; 0.001) compared with the nominal group (5.35 ± 2.59%). There were no significant differences among the groups in the aforementioned parameters at 24, 36, and 48 months, respectively. <b><i>Conclusion:</i></b> While LVEDD, LVEF, 6MWD, and NYHA were significantly improved in ECHO, ECG, and QuickOpt at 6 months, there were no significant improvements in any of the groups at 12, 24, and 48 months. These findings suggested that the long-term effect of the four CRT methods for heart failure was not significantly different.
Diagnostic Value of Different Noninvasive Criteria of Latent Myocarditis in Comparison with Myocardial Biopsy
Authors: Blagova Olga , Osipova Yuliya , Nedostup Alexander , Kogan Evgeniya , Zaitsev Alexander , Fomin Victor 
Published: June 2019

<b><i>Purpose:</i></b> The aim of this study was to quantify the value of various clinical, laboratory, and instrumental signs in the diagnosis of myocarditis in comparison with morphological studies of the myocardium. <b><i>Methods:</i></b> In 100 patients (65 men, 44.7 ± 12.5 years old) with “idiopathic” arrhythmias (<i>n</i> = 20) and dilated cardiomyopathy (DCM; <i>n</i> = 80), we performed the following: 71 endomyocardial biopsies (EMB), 13 intraoperative biopsies, 5 studies of explanted hearts, and 11 autopsies with virus investigation (real-time PCR) of the blood and myocardium. Antiheart antibodies (AHA) were also measured as well as cardiac CT (<i>n</i> = 45), MRI (<i>n</i> = 25), and coronary angiography (<i>n</i> = 47). The comparison group included 50 patients (25 men, 53.7 ± 11.7 years old) with noninflammatory heart diseases who underwent open heart surgery. <b><i>Results:</i></b> Active/borderline myocarditis was diagnosed in 76.0% of the study group and in 21.6% of patients in the comparison group (<i>p</i> &#x3c; 0.001). The myocardial viral genome was observed more frequently in patients in the comparison group than in the study group (65.0 and 40.2%; <i>p</i> &#x3c; 0.01). We evaluated the diagnostic value of noninvasive markers of myocarditis. The panel of AHA had the greatest importance in the identification of myocarditis: sensitivity was 81.5%, and the positive and negative predictive values were 75.0 and 60.5%. This defined the diagnostic value of noninvasive markers of myocarditis and established a diagnostic algorithm providing an individual assessment of the likelihood of myocarditis development. <b><i>Conclusion:</i></b> AHA have the greatest significance in the diagnosis of latent myocarditis in patients with “idiopathic” arrhythmias and DCM. The use of a complex of noninvasive criteria allows the probability of myocarditis to be estimated and the indications for EMB to be determined.
Association of Physician Specialty With Long-Term Implantable Cardioverter-Defibrillator Complication and Reoperations Rates
Authors: Chui Philip W. , Wang Yongfei , Ranasinghe Isuru , Mitiku Teferi Y. , Seto Arnold H. , Rosman Lindsey , Lampert Rachel , Minges Karl E. , Enriquez Alan D. , Curtis Jeptha P. 
Published: June 2019

Background:
Patients undergoing implantable cardioverter-defibrillator (ICD) implantations have high rates of long-term device-related complications and reoperations. Whether physician specialty training is associated with differences in long-term outcomes following ICD implantation is unclear.

Methods and Results:

We linked data from the National Cardiovascular Data Registry ICD Registry with Medicare fee-for-service claims to identify physicians who performed ≥10 index ICDs from 2006 to 2009. We used data from the American Board of Medical Specialties to group the specialty of the implanting physician into mutually exclusive categories: electrophysiologists, interventional cardiologists, general cardiologists, thoracic surgeons, and other specialties. Primary outcomes were long-term device-related complications requiring reoperations or hospitalizations and reoperations for reasons other than complications. We compared the cumulative incidence rates and case-mix adjusted rates of long-term outcomes of index ICD implantations across physician specialties. Our analysis had a median follow-up of 47 months and included 107 966 index ICD implantations. Electrophysiologists had the lowest rates of incident long-term device-related complications (14.1%; interventional cardiologists, 15.3%; general cardiologists, 15.4%; thoracic surgeons, 16.4%; other specialists, 15.2%;
P
<0.001) and reoperations for reasons other than complications (electrophysiologists, 16.7%; interventional cardiologists, 17.0%; general cardiologists, 18.0%; thoracic surgeons, 18.4%; other specialists, 18.0%;
P
<0.001). Compared with patients whose ICDs were implanted by electrophysiologists, patients with implantations performed by nonelectrophysiologists were at higher risk of having long-term device-related complications (relative risk for interventional cardiologists: 1.16 [95% CI, 1.08–1.25]; general cardiologists: 1.13 [1.08–1.18]; thoracic surgeons: 1.20 [1.06–1.37]; all
P
<0.001, but not other specialists: 1.08 [0.99–1.17];
P
=0.07). Compared to patients with implantations performed by electrophysiologists, patients with implantations performed by general cardiologists and thoracic surgeons were at higher risk of reoperation for noncomplication causes (relative risk for general cardiologists: 1.10 [1.05–1.15]; thoracic surgeons: 1.16 [1.00–1.33]; both
P
<0.05).

Conclusions:
Patients with ICD implantations performed by electrophysiologists had the lowest risks of having long-term device-related complications and reoperations for noncomplication causes. Consideration of physician specialty before ICD implantation may represent an opportunity to minimize long-term adverse outcomes.
Oral Aspects: A Performative Approach to 1QM
Authors: Haigh Rebekah 
Published: June 2019

AbstractAs the product of a textual community imbedded in an oral culture, the War Scroll can be rewardingly approached as a composition intended for a community of hearers. Indeed, this article demonstrates that 1QM retained an orally fluid textuality and preserves a variety of textual indicators of performativity: hints of oral engagement, accumulation of imitable practices, and reliance on rhetorical techniques suited to the ear. In examining the performative potentials in the War Scroll’s prescriptive (cols. 1–9), prayer (cols. 10–14), and dramatic (cols. 15–19) material, I argue that 1QM can be understood as a spoken text, one which lends itself to performance and embodiment.
Beyond Anachronism: Histories of International Law and Global Legal Politics
Authors: Benton Lauren 
Published: June 2019

Abstract
This article presents a critique of recent writings, mainly by Anne Orford, of historical methodologies in international law as supposedly focused on rooting out anachronism and separating history from the politics of the present. First, the article shows that this (mis)characterization of historical methods is based on a misreading of the work of Quentin Skinner and the Cambridge School. Second, it argues that Orford errs in assuming that the Cambridge School is representative of historical approaches. The article exposes this error by tracing key strands of socio-legal study of global legal history. That literature has generated new insights about such topics as vernacular discourses of international law and the influence of patterns of colonial politics on global ordering. This new global legal history takes ‘legal politics’ as its object of analysis while merging the study of praxis and theory in the history of international law.
Freebooters and Free Traders: English Colonial Prize Jurisdiction in the West Indies 1655–1670
Authors: Kari Ville 
Published: June 2019

Abstract
Colonial prize courts provided two significant contributions to the English imperial efforts in the West Indies. First, they played a key role in the enforcement of the new colonial power’s own trade monopoly against foreign interlopers and smugglers. Secondly, they helped the newcomer empire to rein in the buccaneers and capers who had populated the Caribbean for decades and to re-deploy them as commissioned privateers.
This paper explores in detail the emergence of the British colonial prize jurisdiction after the English conquest of Jamaica in 1655. It shows how colonial prize courts emerged organically from the English expansion in the West Indies, with powers and duties assigned incrementally to colonial administrators to address the practical needs of the growing empire in breaking the Spanish trade monopoly and establishing its own.