bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of Saturated Coral Aggregate and Shrinkage Reducing Admixture on the Autogenous Shrinkage of Ultrahigh Performance Concrete
Authors: Liu Jinming , Ou Zhongwen , Mo Jinchuan , Chen Yuzhuo , Guo Tong , Deng Wei
Published: July 2017

The use of saturated coral aggregate (SCA) as practical replacement of quartz sand has been shown to effectively mitigate the autogenous shrinkage in ultrahigh performance concrete (UHPC). The autogenous deformation, the compressive strength, the flexural strength, and the hydration property development of paste with different shrinkage means were tested. Three different methods were evaluated to mitigate the autogenous shrinkage: SCA, shrinkage reducing admixture (SRA), and the mixture of SCA and SRA (SRA-SCA). It was found that SCA and SRA have all the effective ways to reduce the shrinkage deformation, and SRA-SCA was the most effective in mitigating the shrinkage. The autogenous shrinkage of UHPC was restrained, when the SCA dosage was 44%, the SRA dosage was 0.8%, the SCA content was 26%, the SRA dosage was 2.4%, the SCA content was 18%, the SRA content was 2.4%, or the SCA dosage was 26%. The mechanical properties were deteriorated by the addition of SCA, while the compressive strength was still higher than 90 MPa at 28 days even though the replacement ratio of SCA was up to 50%. Furthermore, internal curing by means of SCA was proved to be a successful way to mitigate autogenous shrinkage, after the tests.
The Antimicrobial Peptide Human Beta-Defensin-3 Is Induced by Platelet-Released Growth Factors in Primary Keratinocytes
Authors: Bayer Andreas , Lammel Justus , Tohidnezhad Mersedeh , Lippross Sebastian , Behrendt Peter , Klüter Tim , Pufe Thomas , Cremer Jochen , Jahr Holger , Rademacher Franziska , Gläser Regine , Harder Jürgen
Published: July 2017

Platelet-released growth factors (PRGF) and its related clinically used formulations (e.g., Vivostat Platelet-Rich Fibrin (PRF®)) contain a variety of chemokines, cytokines, and growth factors and are therefore used to support healing of chronic, hard-to-heal, or infected wounds. Human beta-defensin-3 (hBD-3) is an antimicrobial peptide inducibly expressed in human keratinocytes especially upon wounding. The potent antimicrobial activity of hBD-3 together with its wound closure-promoting activities suggests that hBD-3 may play a crucial role in wound healing. Therefore, we analyzed the influence of PRGF on hBD-3 expression in human primary keratinocytes in vitro. In addition, we investigated the influence of Vivostat PRF on hBD-3 expression in artificially generated human skin wounds in vivo. PRGF treatment of primary keratinocytes induced a significant, concentration- and time-dependent increase in hBD-3 gene expression which was partially mediated by the epidermal growth factor receptor (EGFR). In line with these cell culture data, in vivo experiments revealed an enhanced hBD-3 expression in experimentally produced human wounds after the treatment with Vivostat PRF. Thus, the induction of hBD-3 may contribute to the beneficial effects of thrombocyte concentrate lysates in the treatment of chronic or infected wounds.
Anomalous Diffusion with an Irreversible Linear Reaction and Sorption-Desorption Process
Authors: dos Santos Maike A. F. , Lenzi Marcelo K. , Lenzi Ervin K.
Published: July 2017

We investigate the diffusion of two different species in a semi-infinite medium considering the presence of linear reaction terms. The dynamics for these species is governed by fractional diffusion equations. We also consider the presence of an adsorption-desorption boundary condition. The solutions for this system are found in terms of the H function of Fox and by analyzing the behavior of the mean square displacement a rich class of diffusion processes is verified. In this sense, we show how the surface effects modify the bulk dynamics and promote an anomalous diffusion of system.
Evolutionary Game Algorithm for Image Segmentation
Authors: Zhong Jin , Wu Hao
Published: July 2017

The traditional two-dimensional Otsu algorithm only considers the limitations of the maximum variance of between-cluster variance of the target class and background class; this paper proposes evolutionary game improved algorithm. Algorithm takes full consideration of own pixel cohesion of target and background. It can meet the same of maximum variance of between-cluster variance. To ensure minimum threshold discriminant function within the variance, this kind of evolutionary game algorithm searching space for optimal solution is applied. Experimental results show that the method proposed in this paper makes the detail of segmentation image syllabify and has better antijamming capability; the improved genetic algorithm which used searching optimal solution has faster convergence speed and better global search capability.
Mathematical Model for Electric Field Sensor Based on Whispering Gallery Modes Using Navier’s Equation for Linear Elasticity
Authors: Ali Amir R. , Kamel Mohamed A.
Published: July 2017

This paper presents and verifies the mathematical model of an electric field senor based on the whispering gallery mode (WGM). The sensing element is a dielectric microsphere, where the light is used to tune the optical modes of the microsphere. The light undergoes total internal reflection along the circumference of the sphere; then it experiences optical resonance. The WGM are monitored as sharp dips on the transmission spectrum. These modes are very sensitive to morphology changes of the sphere, such that, for every minute change in the sphere’s morphology, a shift in the transmission spectrum will happen and that is known as WGM shifts. Due to the electrostriction effect, the applied electric field will induce forces acting on the surface of the dielectric sphere. In turn, these forces will deform the sphere causing shifts in its WGM spectrum. The applied electric field can be obtained by calculating these shifts. Navier’s equation for linear elasticity is used to model the deformation of the sphere to find the WGM shift. The finite element numerical studies are performed to verify the introduced model and to study the behavior of the sensor at different values of microspheres’ Young’s modulus and dielectric constant. Furthermore, the sensitivity and resolution of the developed WGM electric filed sensor model will be presented in this paper.
A Novel Functional Splice Variant of AKT3 Defined by Analysis of Alternative Splice Expression in HPV-Positive Oropharyngeal Cancers
Authors: Guo Theresa , Sakai Akihiro , Afsari Bahman , Considine Michael , Danilova Ludmila , Favorov Alexander V. , Yegnasubramanian Srinivasan , Kelley Dylan Z. , Flam Emily , Ha Patrick K. , Khan Zubair , Wheelan Sarah J. , Gutkind J. Silvio , Fertig Elana J. , Gaykalova Daria A. , Califano Joseph
Published: July 2017

The incidence of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) has increased more than 200% in the past 20 years. Recent genetic sequencing efforts have elucidated relevant genes in head and neck cancer, but HPV-related tumors have consistently shown few DNA mutations. In this study, we sought to analyze alternative splicing events (ASE) that could alter gene function independent of mutations. To identify ASE unique to HPV-related tumors, RNA sequencing was performed on 46 HPV-positive OPSCC and 25 normal tissue samples. A novel algorithm using outlier statistics on RNA-sequencing junction expression identified 109 splicing events, which were confirmed in a validation set from The Cancer Genome Atlas. Because the most common type of splicing event identified was an alternative start site (39%), MBD-seq genome-wide CpG methylation data were analyzed for methylation alterations at promoter regions. ASE in six genes showed significant negative correlation between promoter methylation and expression of an alternative transcriptional start site, including AKT3. The novel AKT3 transcriptional variant and methylation changes were confirmed using qRT-PCR and qMSP methods. In vitro silencing of the novel AKT3 variant resulted in significant growth inhibition of multiple head and neck cell lines, an effect not observed with wild-type AKT3 knockdown. Analysis of ASE in HPV-related OPSCC identified multiple alterations likely involved in carcinogenesis, including a novel, functionally active transcriptional variant of AKT3. Our data indicate that ASEs represent a significant mechanism of oncogenesis with untapped potential for understanding complex genetic changes that result in the development of cancer. Cancer Res; 77(19); 5248–58. ©2017 AACR.
89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors
Authors: Bensch Frederike , Lamberts Laetitia E. , Smeenk Michaël M. , Jorritsma-Smit Annelies , Lub-de Hooge Marjolijn N. , Terwisscha van Scheltinga Anton G.T. , de Jong Johan R. , Gietema Jourik A. , Schröder Carolien P. , Thomas Marlene , Jacob Wolfgang , Abiraj Keelara , Adessi Celine , Meneses-Lorente Georgina , James Ian , Weisser Martin , Brouwers Adrienne H. , de Vries Elisabeth G.E.
Published: July 2017

Purpose: We evaluated biodistribution and tumor targeting of 89Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)–targeting monoclonal antibody.

Experimental Design: Twenty patients with histologically confirmed HER3-expressing tumors received 89Zr-lumretuzumab and underwent positron emission tomography (PET). In part A, 89Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab, and scans were performed 2, 4, and 7 days after injection to determine optimal imaging conditions. In part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV).

Results: Optimal PET conditions were found to be 4 and 7 days after administration of 89Zr-lumretuzumab with 100-mg unlabeled lumretuzumab. At baseline using 100-mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (±1.9) at 4 days after injection. SUVmean values for normal blood, liver, lung, and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n = 7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (±8.2), 10.0% (±16.5), and 24.6% (±20.9) at PD-active doses of 400, 800, and 1,600 mg, respectively, when compared with baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400-mg lumretuzumab.

Conclusions: PET imaging showed biodistribution and tumor-specific 89Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased 89Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses. Clin Cancer Res; 23(20); 6128–37. ©2017 AACR.
Molecular Screening for Cancer Treatment Optimization (MOSCATO-01) in Pediatric Patients: A Single-Institutional Prospective Molecular Stratification Trial
Authors: Harttrampf Anne C. , Lacroix Ludovic , Deloger Marc , Deschamps Frederic , Puget Stephanie , Auger Nathalie , Vielh Philippe , Varlet Pascale , Balogh Zsofia , Abbou Samuel , Allorant Adrien , Valteau-Couanet Dominique , Sarnacki Sabine , Gamiche-Rolland Louise , Meurice Guillaume , Minard-Colin Veronique , Grill Jacques , Brugieres Laurence , Dufour Christelle , Gaspar Nathalie , Michiels Stefan , Vassal Gilles , Soria Jean-Charles , Geoerger Birgit
Published: July 2017

Purpose: This single-institutional feasibility study prospectively characterized genomic alterations in recurrent or refractory solid tumors of pediatric patients to select a targeted therapy.

Experimental Design: Following treatment failure, patients with signed consent and ages above 6 months, underwent tumor biopsy or surgical resection of primary or metastatic tumor site. These newly acquired samples were analyzed by comparative genomic hybridization array, next-generation sequencing for 75 target genes, whole-exome and RNA sequencing. Biological significance of the alterations and suggestion of most relevant targeted therapies available were discussed in a multidisciplinary tumor board.

Results: From December 2012 to January 2016, 75 patients were included, 73 patients underwent 79 interventions, 56 of which were research biopsies with a low complication rate. All patients were pretreated, 37.0% had a brain tumor, and 63.0% had an extra-cranial solid tumor. Median tumor cell content was 70% (range, 0%–100%). Successful molecular analysis in 69 patients detected in 60.9% of patients an actionable alteration in various oncogenic pathways (42.4% with copy-number change, 33.3% with mutation, 2.1% with fusion), and change in diagnosis in three patients. Fourteen patients received 17 targeted therapies; two had received a matched treatment before inclusion.

Conclusions: Research biopsies are feasible in advanced pediatric malignancies that exhibit a considerable amount of potentially actionable alterations. Genetic events affecting different cancer hallmarks and limited access to targeted agents within pediatric clinical trials remain the main obstacles that are addressed in our two subsequent precision medicine studies MAPPYACTS and AcSé-ESMART. Clin Cancer Res; 23(20); 6101–12. ©2017 AACR.
Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making
Authors: Yap Christina , Billingham Lucinda J. , Cheung Ying Kuen , Craddock Charlie , O'Quigley John
Published: July 2017

The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate, or stop early), using all the accumulated information. After specifying a model with favorable statistical properties, we utilize the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgments. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified continual reassessment method is illustrated in an acute myeloid leukemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose update. In the illustrated trial, the seamless, clear transition for each dose recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators. Clin Cancer Res; 23(24); 7440–7. ©2017 AACR.
Implementation of a Model-Based Design in a Phase Ib Study of Combined Targeted Agents
Authors: Wages Nolan A. , Portell Craig A. , Williams Michael E. , Conaway Mark R. , Petroni Gina R.
Published: July 2017

In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations. Clin Cancer Res; 23(23); 7158–64. ©2017 AACR.
Direct Metabolic Interrogation of Dihydrotestosterone Biosynthesis from Adrenal Precursors in Primary Prostatectomy Tissues
Authors: Dai Charles , Chung Yoon-Mi , Kovac Evan , Zhu Ziqi , Li Jianneng , Magi-Galluzzi Cristina , Stephenson Andrew J. , Klein Eric A. , Sharifi Nima
Published: July 2017

Purpose: A major mechanism of castration-resistant prostate cancer (CRPC) involves intratumoral biosynthesis of dihydrotestosterone (DHT) from adrenal precursors. We have previously shown that adrenal-derived androstenedione (AD) is the preferred substrate over testosterone (T) for 5α-reductase expressed in metastatic CRPC, bypassing T as an obligate precursor to DHT. However, the metabolic pathway of adrenal-derived DHT biosynthesis has not been rigorously investigated in the setting of primary disease in the prostate.

Experimental Design: Seventeen patients with clinically localized prostate cancer were consented for fresh tissues after radical prostatectomy. Prostate tissues were cultured ex vivo in media spiked with an equimolar mixture of AD and T, and stable isotopic tracing was employed to simultaneously follow the enzymatic conversion of both precursor steroids into nascent metabolites, detected by liquid chromatography-tandem mass spectrometry. CRPC cell line models and xenograft tissues were similarly assayed for comparative analysis. A tritium-labeled steroid radiotracing approach was used to validate our findings.

Results: Prostatectomy tissues readily 5α-reduced both T and AD. Furthermore, 5α-reduction of AD was the major directionality of metabolic flux to DHT. However, AD and T were comparably metabolized by 5α-reductase in primary prostate tissues, contrasting the preference exhibited by CRPC in which AD was favored over T. 5α-reductase inhibitors effectively blocked the conversion of AD to DHT.

Conclusions: Both AD and T are substrates of 5α-reductase in prostatectomy tissues, resulting in two distinctly nonredundant metabolic pathways to DHT. Furthermore, the transition to CRPC may coincide with a metabolic switch toward AD as the favored substrate. Clin Cancer Res; 23(20); 6351–62. ©2017 AACR.
TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: An Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence
Authors: Reuben Alexandre , Gittelman Rachel , Gao Jianjun , Zhang Jiexin , Yusko Erik C. , Wu Chang-Jiun , Emerson Ryan , Zhang Jianhua , Tipton Christopher , Li Jun , Quek Kelly , Gopalakrishnan Vancheswaran , Chen Runzhe , Vence Luis M. , Cascone Tina , Vignali Marissa , Fujimoto Junya , Rodriguez-Canales Jaime , Parra Edwin R. , Little Latasha D. , Gumbs Curtis , Forget Marie-Andrée , Federico Lorenzo , Haymaker Cara , Behrens Carmen , Benzeno Sharon , Bernatchez Chantale , Sepesi Boris , Gibbons Don L. , Wargo Jennifer A. , William William N. , Swisher Stephen , Heymach John V. , Robins Harlan , Lee J. Jack , Sharma Padmanee , Allison James P. , Futreal P. Andrew , Wistuba Ignacio I. , Zhang Jianjun
Published: July 2017

Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens, were shown to alter tumor immunogenicity through T-cell responses. Here, we performed sequencing of the T-cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T-cell density and clonality with the majority of T-cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T-cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T-cell repertoire heterogeneity.

Significance: The present study provides insights into the ITH of the T-cell repertoire in localized lung adenocarcinomas and its potential biological and clinical impact. The results suggest that T-cell repertoire ITH may be tightly associated to genomic ITH and disease relapse. Cancer Discov; 7(10); 1088–97. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1047
Fibroblast Growth Factor 23 Predicts Mortality and End-Stage Renal Disease in a Canadian Asian Population with Chronic Kidney Disease
Authors: Jialal Ishwarlal , Camacho Fernando , Nathoo Bharat , Tam Paul , Pahwa Roma , Wu George G.
Published: July 2017

Background: Chronic kidney disease (CKD) is a leading cause of morbidity and mortality. Biomarkers that predict end-stage renal disease (ESRD) and/or mortality could usher in new therapeutics to halt this onslaught. While fibroblast growth factor (FGF)23 can predict both ESRD and mortality, it has not been studied in North American CKD patients of Asian ethnicity. Method: This is a prospective investigation about the role of FGF23 in 998 Canadian patients of Asian descent with CKD defined by an estimated glomerular filtration rate (eGFR) <60 mL/min/m2 and followed up for 3 years. Results: The mean age of patients was 68.9 years and 68.3% were males. The mean (range) eGFR, and median FGF23 were 40.2 (11.0-59.0) mL/min and 154.1 (7.0-7,823.0) RU/mL, respectively. Over the 3 years, higher values of FGF23 levels at baseline were associated with higher risk of ESRD (hazard ratio [HR] for log[Fgf23] = 2.16 [95% CI 1.20-3.89]). Despite the short follow-up, 42 patients died due to cardiovascular diseases (38.8%), cancer (14.9%), and infections (12.7%). Log-FGF23 levels were independently associated with death, HR 1.94, 95% CI 1.24-3.03. Mortality risk increased in FGF23 subgroups from <100 to >400 RU/mL. In a time-changing covariate analysis, serial log-FGF23 levels over the 3 years predicted mortality with a HR of 2.66 (95% CI 1. 79-3.95). Conclusion: In a Canadian Asian population with CKD, FGF23 levels obtained at 6-monthly intervals for 3 years predicted ESRD and mortality suggesting that it is also a risk marker in Asians.
Lanthanum Chloride Inhibits LPS Mediated Expressions of Pro-Inflammatory Cytokines and Adhesion Molecules in HUVECs: Involvement of NF-κB-Jmjd3 Signaling
Authors: Chen Xia , Xiu Min , Xing Juanjuan , Yu Shaoqing , Min Dinghong , Guo Fei
Published: July 2017

Background/Aims: To investigate the regulation of LaCl3 on lipopolysaccharides (LPS)-induced pro-inflammatory cytokines and adhesion molecules in human umbilical vein endothelial cells (HUVECs). Methods: Primary cultured HUVECs were pretreated with 2.5 µM LaCl3 for 30 min followed by 1 µg/ml LPS for 2 h. Pro-inflammatory cytokine and adhesion molecule expressions were determined by real-time RT-PCR and ELISA. NF-κB/p65 nuclear translocation was examined by immunofluorescence and immuno-blot, and its DNA-binding activity was measured by chemiluminescence. Recruitment of NF-κB/p65, Jmjd3, and H3K27me3 to gene promoter regions was determined by ChIP-qPCR. Results: LaCl3 exhibited no cytotoxic effects to primary HUVECs at concentrations ≤ 50 µM. LPS-mediated TNF-α, IL-1β, IL-6, MMP-9, and ICAM-1 production, nuclear translocation, and DNA-binding activity of NF-κB/p65, as well as Jmjd3 expression, were all reduced significantly by LaCl3. Furthermore, LaCl3 treatment significantly impaired LPS-induced enrichment of NF-κB/p65 to the promoter regions of TNF-α, MMP-9, IL-1β, ICAM-1, and IL-6; and of Jmjd3 to the promoter regions of TNF-α, MMP-9, IL-1β, and IL-6. H3K27me3 abundance in the promoter regions of TNF-α and ICAM-1 increased significantly in following LaCl3 treatment. Conclusion: LaCl3 inhibits pro-inflammatory cytokine and adhesion molecule expressions induced by LPS in HUVECs. NF-κB and histone demethylase Jmjd3 are involved in this effect.
Multicellular Transcriptional Analysis of Mammalian Heart Regeneration
Authors: Quaife-Ryan Gregory A. , Sim Choon Boon , Ziemann Mark , Kaspi Antony , Rafehi Haloom , Ramialison Mirana , El-Osta Assam , Hudson James E. , Porrello Enzo R.
Published: July 2017

Background:

The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we assemble a transcriptomic framework of multiple cardiac cell populations during postnatal development and following injury, which enables comparative analyses of the regenerative (neonatal) versus nonregenerative (adult) state for the first time.

Methods:

Cardiomyocytes, fibroblasts, leukocytes, and endothelial cells from infarcted and noninfarcted neonatal (P1) and adult (P56) mouse hearts were isolated by enzymatic dissociation and fluorescence-activated cell sorting at day 3 following surgery. RNA sequencing was performed on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair, and regeneration. To complement our transcriptomic data, we also surveyed the epigenetic landscape of cardiomyocytes during postnatal maturation by performing deep sequencing of accessible chromatin regions by using the Assay for Transposase-Accessible Chromatin from purified mouse cardiomyocyte nuclei (P1, P14, and P56).

Results:

Profiling of cardiomyocyte and nonmyocyte transcriptional programs uncovered several injury-responsive genes across regenerative and nonregenerative time points. However, the majority of transcriptional changes in all cardiac cell types resulted from developmental maturation from neonatal stages to adulthood rather than activation of a distinct regeneration-specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state. In contrast, cardiomyocytes failed to reactivate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during postnatal maturation.

Conclusions:

This work provides a comprehensive framework and transcriptional resource of multiple cardiac cell populations during cardiac development, repair, and regeneration. Our findings define a regulatory program underpinning the neonatal regenerative state and identify alterations in the chromatin landscape that could limit reinduction of the regenerative program in adult cardiomyocytes.
Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate
Authors: Hughan Kara S. , Wendell Stacy Gelhaus , Delmastro-Greenwood Meghan , Helbling Nicole , Corey Catherine , Bellavia Landon , Potti Gopal , Grimes George , Goodpaster Bret , Kim-Shapiro Daniel B. , Shiva Sruti , Freeman Bruce A. , Gladwin Mark T.
Published: July 2017

Dietary NO
3
−
(nitrate) and NO
2
−
(nitrite) support ˙NO (nitric oxide) generation and downstream vascular signaling responses. These nitrogen oxides also generate secondary nitrosating and nitrating species that react with low molecular weight thiols, heme centers, proteins, and unsaturated fatty acids. To explore the kinetics of NO
3
−
and NO
2
−
metabolism and the impact of dietary lipid on nitrogen oxide metabolism and cardiovascular responses, the stable isotopes Na
15
NO
3
and Na
15
NO
2
were orally administered in the presence or absence of conjugated linoleic acid (cLA). The reduction of
15
NO
2
−
to
15
NO was indicated by electron paramagnetic resonance spectroscopy detection of hyperfine splitting patterns reflecting
15
NO-deoxyhemoglobin complexes. This formation of
15
NO also translated to decreased systolic and mean arterial blood pressures and inhibition of platelet function. Upon concurrent administration of cLA, there was a significant increase in plasma cLA nitration products 9- and 12-
15
NO
2
-cLA. Coadministration of cLA with
15
NO
2
−
also impacted the pharmacokinetics and physiological effects of
15
NO
2
−
, with cLA administration suppressing plasma NO
3
−
and NO
2
−
levels, decreasing
15
NO-deoxyhemoglobin formation, NO
2
−
inhibition of platelet activation, and the vasodilatory actions of NO
2
−
, while enhancing the formation of 9- and 12-
15
NO
2
-cLA. These results indicate that the biochemical reactions and physiological responses to oral
15
NO
3
−
and
15
NO
2
−
are significantly impacted by dietary constituents, such as unsaturated lipids. This can explain the variable responses to NO
3
−
and NO
2
−
supplementation in clinical trials and reveals dietary strategies for promoting the generation of pleiotropic nitrogen oxide-derived lipid signaling mediators.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01681836.
Addition of 24‐Hour Heart Rate Variability Parameters to the Cardiovascular Health Study Stroke Risk Score and Prediction of Incident Stroke: The Cardiovascular Health Study
Authors: Bodapati Rohan K. , Kizer Jorge R. , Kop Willem J. , Kamel Hooman , Stein Phyllis K.
Published: July 2017

Background

Heart rate variability (
HRV
) characterizes cardiac autonomic functioning. The association of
HRV
with stroke is uncertain. We examined whether 24‐hour
HRV
added predictive value to the Cardiovascular Health Study clinical stroke risk score (
CHS
‐
SCORE
), previously developed at the baseline examination.

Methods and Results

N=884 stroke‐free
CHS
participants (age 75.3±4.6), with 24‐hour Holters adequate for
HRV
analysis at the 1994–1995 examination, had 68 strokes over ≤8 year follow‐up (median 7.3 [interquartile range 7.1–7.6] years). The value of adding
HRV
to the
CHS
‐
SCORE
was assessed with stepwise Cox regression analysis. The
CHS
‐
SCORE
predicted incident stroke (
HR
=1.06 per unit increment,
P
=0.005). Two
HRV
parameters, decreased coefficient of variance of
NN
intervals (
CV
%,
P
=0.031) and decreased power law slope (
SLOPE
,
P
=0.033) also entered the model, but these did not significantly improve the c‐statistic (
P
=0.47). In a secondary analysis, dichotomization of
CV
% (
LOWCV
% ≤12.8%) was found to maximally stratify higher‐risk participants after adjustment for
CHS
‐
SCORE
. Similarly, dichotomizing
SLOPE
(
LOWSLOPE
<−1.4) maximally stratified higher‐risk participants. When these
HRV
categories were combined (eg,
HIGHCV
% with
HIGHSLOPE
), the c‐statistic for the model with the
CHS
‐
SCORE
and combined
HRV
categories was 0.68, significantly higher than 0.61 for the
CHS
‐
SCORE
alone (
P
=0.02).

Conclusions

In this sample of older adults, 2
HRV
parameters,
CV
% and power law slope, emerged as significantly associated with incident stroke when added to a validated clinical risk score. After each parameter was dichotomized based on its optimal cut point in this sample, their composite significantly improved prediction of incident stroke during ≤8‐year follow‐up. These findings will require validation in separate, larger cohorts.
Added Value of Patient‐Reported Outcome Measures in Stroke Clinical Practice
Authors: Katzan Irene L. , Thompson Nicolas R. , Lapin Brittany , Uchino Ken
Published: July 2017

Background

There is uncertainty regarding the clinical utility of the data obtained from patient‐reported outcome measures (
PROM
s) for patient care. We evaluated the incremental information obtained by
PROM
s compared to the clinician‐reported modified Rankin Scale (
mRS
).

Methods and Results

This was an observational study of 3283 ischemic stroke patients seen in a cerebrovascular clinic from September 14, 2012 to June 16, 2015 who completed the routinely collected
PROM
s: Stroke Impact Scale‐16 (
SIS
‐16),
EQ
‐5D, Patient Health Questionnaire‐9,
PROMIS
Physical Function, and
PROMIS
fatigue. The amount of variation in the
PROM
s explained by
mRS
was determined using r
2
after adjustment for age and level of stroke impairment. The proportion with meaningful change was calculated for patients with ≥2 visits. Concordance with change in the other scales and the ability to discriminate changes in health state as measured by c‐statistic was evaluated for
mRS
versus
SIS
‐16. Correlation between
PROM
s and
mRS
was highest for
SIS
‐16 (
r
=−0.64,
P
<0.01). The r
2
ranged from 0.11 (
PROMIS
fatigue) to 0.56 (
SIS
‐16). Change in scores occurred in 51% with
mRS
and 35% with
SIS
‐16. There was lower agreement and less ability to discriminate change in
mRS
than in
SIS
‐16 with change in the other measures.

Conclusions

PROM
s provide additional valuable information compared to the
mRS
alone in stroke patients seen in the ambulatory setting.
SIS
‐16 may have a better ability to identify change than
mRS
in health status of relevance to the patient.
PROM
s may be a useful addition to
mRS
in the assessment of health status in clinical practice.
Atherogenic Lipoprotein Determinants of Cardiovascular Disease and Residual Risk Among Individuals With Low Low‐Density Lipoprotein Cholesterol
Authors: Lawler Patrick R. , Akinkuolie Akintunde O. , Chu Audrey Y. , Shah Svati H. , Kraus William E. , Craig Damian , Padmanabhan Latha , Glynn Robert J. , Ridker Paul M , Chasman Daniel I. , Mora Samia
Published: July 2017

Background

Levels of LDL (low‐density lipoprotein) cholesterol in the population are declining, and increasing attention is being focused on residual lipid‐related pathways of atherosclerotic cardiovascular disease risk beyond
LDL
cholesterol. Among individuals with low (<130 mg/dL)
LDL
cholesterol, we undertook detailed profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease in 2 populations.

Methods and Results

We performed proton nuclear magnetic resonance spectroscopy to quantify concentrations of
LDL
and VLDL (very low‐density lipoprotein) particle subclasses in 11 984
JUPITER
trial participants (
NCT
00239681). Adjusted Cox models examined cardiovascular disease risk associated with lipoprotein measures according to treatment allocation. Risk (adjusted hazard ratio [95%
CI
] per
SD
increment) among placebo‐allocated participants was associated with total
LDL
particles (1.19 [1.02, 1.38]) and total
VLDL
particles (1.21 [1.04, 1.41]), as well as apolipoprotein B, non–high‐density lipoprotein cholesterol, and triglycerides, but not LDL‐c. Rosuvastatin reduced
LDL
measures but had variable effects on triglyceride and
VLDL
measures. On‐statin levels of the smallest
VLDL
particle subclass were associated with a 68% per‐
SD
(adjusted hazard ratio 1.68 [1.28, 2.22]) increase in residual risk—this risk was related to
VLDL
cholesterol and not triglyceride or larger
VLDL
particles. There was evidence that residual risk prediction during statin therapy could be significantly improved through the inclusion of key
VLDL
measures (Harrell C‐index 0.780 versus 0.712;
P
<0.0001). In an independent, prospective cohort of 4721 individuals referred for cardiac catheterization (
CATHGEN
), similar patterns of lipoprotein‐related risk were observed.

Conclusions

Atherogenic lipoprotein particle concentrations were associated with cardiovascular disease risk when
LDL
cholesterol was low.
VLDL
lipoproteins, particularly the smallest remnant subclass, may represent unused targets for risk prediction and potential therapeutic intervention for reducing residual risk.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
00239681.
Should Bilateral Internal Thoracic Artery Grafting Be Used in Patients After Recent Myocardial Infarction?
Authors: Loberman Dan , Pevni Dmitry , Mohr Rephael , Paz Yosef , Nesher Nahum , Midlij Mohamad Khaled , Ben‐Gal Yanai
Published: July 2017

Background

Bilateral internal thoracic artery grafting (
BITA
) is associated with improved survival. However, surgeons do not commonly use
BITA
in patients after myocardial infarction (
MI
) because survival is good with single
internal thoracic artery grafting
(
SITA
). We aimed to compare the outcomes of
BITA
with those of
SITA
and other approaches in patients with multivessel disease after recent
MI
.

Methods and Results

In total, 938 patients with recent
MI
(<3 months) who underwent
BITA
between 1996 and 2011 were compared with 682 who underwent
SITA
.
SITA
patients were older and more likely to have comorbidities (diabetes mellitus, chronic obstructive pulmonary disease, chronic renal failure, peripheral vascular disease), to be female, and to have had a previous
MI
. Acute
MI
and 3‐vessel disease were more prevalent in the
BITA
group. Operative mortality of
BITA
patients was lower (3.0% versus 5.8%,
P
=0.01), and sternal infections and strokes were similar. Median follow‐up was 15.21 years (range: 0–21.25 years). Survival of
BITA
patients was better (70.3% versus 52.5%,
P
<0.001). Propensity score matching was used to account for differences in preoperative characteristics between groups. Overall, 551 matched pairs had similar preoperative characteristics.
BITA
was a predictor of better survival in the matched groups (hazard ratio: 0.679;
P
=0.002; Cox model). Adjusted survival of emergency
BITA
and
SITA
patients was similar (
hazard ratio:
0.883;
P
=0.447); however, in the nonemergency group,
BITA
was a predictor of better survival (hazard ratio: 0.790;
P
=0.009; Cox model).

Conclusions

This study suggests that survival is better with
BITA
compared with SITA in nonemergency cases after recent
MI,
with proper patient selection.
Intensive Exercise Training Improves Cardiac Electrical Stability in Myocardial‐Infarcted Rats
Authors: Dor‐Haim Horesh , Lotan Chaim , Horowitz Michal , Swissa Moshe
Published: July 2017

Background

Moderate exercise training has been shown to decrease sudden cardiac death post myocardial infarction. However, the effects of intensive exercise are still controversial.

Methods and Results

Fourteen myocardial‐infarcted rats were divided into sedentary (n=8) and intensive training groups (n=6) and 18 sham control rats to sedentary (n=10) and intensive training groups (n=8). Heart rate variability was obtained at weeks 1 and 8. The inducibility of ventricular tachycardia/fibrillation was assessed in a Langendorff system. Fast Fourier transforms were applied on the recorded ventricular tachycardia/fibrillations. Training reduces low to high frequency ratio of heart rate variability at week 8 compared with that at week 1 (
P
<0.05). In isolated hearts, the probability for ventricular tachycardia/fibrillation was decreased from 4.5±0.8% in sedentary controls to 1.56±0.2% in intensive training controls (
P
<0.05) and from 13.5±2.1% in the sedentary group to 5.4±1.2% in the intensive training group (
P
<0.01). Moreover, the pacing current required for ventricular fibrillation induction in the trained groups was increased following exercise (
P
<0.05). Fast Fourier transform analysis of
ECG
findings revealed an exercise‐induced ventricular fibrillation transition from a narrow, single‐peak spectrum at 17 Hz in sedentary controls to a broader range of peaks ranging from 13 to 22 Hz in the intensive training controls.

Conclusions

Intensive exercise in infarcted rats leads to reduced ventricular fibrillation propensity and is associated with normalization of refractoriness and intrinsic spatiotemporal electrical variations.
Focal Cerebral Arteriopathy
Authors: Steinlin Maja , Bigi Sandra , Stojanovski Belinda , Gajera Jay , Regényi Maria , El-Koussy Marwan , Mackay Mark T.
Published: July 2017

Background and Purpose—

Focal cerebral arteriopathy accounts for up to 35% of arterial ischemic stroke (AIS) in children and is the most important predictor of stroke recurrence. The study objective was to compare outcomes for children with focal cerebral arteriopathy treated with combined corticosteroid antithrombotic treatment (CAT) to those receiving antithrombotic treatment (AT) alone.

Methods—

This multicenter retrospective Swiss/Australian cohort study analyzed consecutive children, aged 1 month to 18 years, presenting with first AIS because of a focal cerebral arteriopathy from 2000 to 2014. Children with CAT were compared with those treated with AT. Primary outcome was the presence of neurological deficits at 6 months post–AIS as measured by the Pediatric Stroke Outcome Measure. Secondary outcomes included resolution of stenosis and stroke recurrence. Analysis of covariance was used to adjust for potential confounders (baseline pediatric National Institute of Health Stroke Scale and concomitant acyclovir use).

Results—

A total of 73 children (51% males) were identified, 21 (29%) of whom received CAT. Mean (SD) age at stroke for the entire group was 7.9 years (4.7). Median (interquartile range) pediatric National Institute of Health Stroke Scale was 3 (2.0–8.0) in the CAT group and 5 (3.0–9.0) in the AT group (
P
=0.098). Median (interquartile range) Pediatric Stroke Outcome Measure 6 months post-AIS was 0.5 (0–1.5) in the CAT group compared with 1.0 (0.5–2.0) in the AT group (
P
=0.035), the finding was sustained after adjusting for potential confounders. Complete resolution of stenosis at last MRI was noted in 17 (81%) in the CAT group compared with 24 (59%) in the AT group (
P
=0.197). Stroke recurrence occurred in 1 patient in each group.

Conclusions—

Corticosteroid treatment may provide additional benefit over AT for improved neurological outcome in childhood AIS because of focal cerebral arteriopathy. Larger prospective studies are warranted to further investigate these differences and understand mechanisms by which steroids modify outcome.
Risk Factors of Sudden Death From Subarachnoid Hemorrhage
Authors: Lindbohm Joni Valdemar , Kaprio Jaakko , Jousilahti Pekka , Salomaa Veikko , Korja Miikka
Published: July 2017

Background and Purpose—

One in every 4 subarachnoid hemorrhage (SAH) patients dies suddenly outside hospital, but most SAH risk factor studies focus on hospitalized patients. We studied the differences in risk factors between hospitalized SAH and sudden-death SAH patients.

Methods—

The population-based FINRISK study cohort of 65 521 individuals was followed up for 1.52 million person-years. The Cox proportional hazards model calculated hazard ratios (HRs), with all analyses adjusted for known SAH risk factors, marital status, and socioeconomic status. A competing risks model analyzed differences in risk factors between hospitalized SAHs and sudden-death SAHs.

Results—

We identified 98 sudden-death SAHs and 445 hospitalized SAHs confirmed by autopsy or by standard SAH diagnostics. Increase by 5 cigarettes smoked per day elevated sudden-death SAH risk (HR, 1.28; 95% confidence interval [CI], 1.17–1.39) more than hospitalized SAH risk (HR, 1.19; 95% CI, 1.13–1.24;
P
=0.05 for difference). Per SD (21.4 mm Hg) increase, systolic blood pressure elevated risk of sudden-death SAH (HR, 1.34; 95% CI, 1.09–1.65) more than risk for hospitalized SAH (HR, 1.25; (95% CI, 1.12–1.38;
P
=0.05 for difference). Participants living without a partner were at elevated risk of sudden-death SAH (HR, 2.09; 95% CI, 1.33–3.28) but not of hospitalized SAH. No sudden-death SAHs occurred in normotensive never smokers aged <50 years.

Conclusions—

Sudden-death SAH risk seems to be highest among those individuals with the most adverse risk factor profiles and among those who live without a partner, whereas it is rare among normotensive never smokers aged <50 years.
Skeptical but Adapting: What Midwestern Farmers Say about Climate Change
Authors: Doll Julie E. , Petersen Brian , Bode Claire
Published: July 2017

Farmers stand to be greatly affected by changes in the climate, necessitating adaptive responses, yet little is documented on how U.S. Midwestern farmers understand and perceive climate change adaptation. Eight focus groups with 53 Michigan farmers were conducted in 2011–12 to better understand the following: 1) what do farmers think about the relationship between climate change and agriculture, 2) what differentiates normal weather-related management from climate change adaptation actions, and 3) how do farmers understand the term “climate change adaptation.” Farmers expressed skepticism at global climate change yet conveyed specific details about the local changes in climate they are experiencing on their farms. They were not able to clearly define the term “climate change adaptation” but did note specific adaptive actions they have already implemented. The farmers explained that nonclimate factors were of more concern to them when making management decisions, and they showed reactive (not proactive) actions toward adaptation. Farmers noted that any action they take has to address their specific situation, suggesting that generalized adaptation actions and language might not resonate with them. Building on quantitative surveys conducted by others, the findings in this paper contribute to ongoing efforts to more effectively assess farmers’ perceptions related to climate change adaptation and to use that understanding to promote education, outreach, research, and public policies to more proactively address the consequences posed by climate change.
A Storm in a Teacup? Hurricanes and Sugar Prices in the First Half of the Nineteenth Century
Authors: Bensassi Sami , Mohan Preeya , Strobl Eric
Published: July 2017

This paper investigates the impact of hurricanes in the Caribbean on sugar prices in Britain between 1815 and 1841. The authors expect the news of hurricanes arriving at British harbors to drive up sugar prices mainly because the market anticipated that the supply of sugar from the Caribbean colonies would drop dramatically in the near future. The econometric results suggest a significant rise in prices due to hurricanes. Moreover this study finds that the lag between the hurricane strike and its transmission into sugar prices on the London market decreased over the sample period. This latter result might be explained by the technological innovations marking this era, where technological progress in transport reduced the time required for information to cross the Atlantic, making markets more reactive to the news of supply shocks.
Empirical Underidentification with the Bifactor Model: A Case Study
Authors: Green Samuel , Yang Yanyun
Published: July 2017

Bifactor models are commonly used to assess whether psychological and educational constructs underlie a set of measures. We consider empirical underidentification problems that are encountered when fitting particular types of bifactor models to certain types of data sets. The objective of the article was fourfold: (a) to allow readers to gain a better general understanding of issues surrounding empirical identification, (b) to offer insights into empirical underidentification with bifactor models, (c) to inform methodologists who explore bifactor models about empirical underidentification with these models, and (d) to propose strategies for structural equation model users to deal with underidentification problems that can emerge when applying bifactor models.