bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectrum-Based Fault Localization in Model Transformations
Authors: Troya Javier , Segura Sergio , Parejo Jose Antonio , Ruiz-Cortés Antonio
Published: September 2018

Model transformations play a cornerstone role in Model-Driven Engineering (MDE), as they provide the essential mechanisms for manipulating and transforming models. The correctness of software built using MDE techniques greatly relies on the correctness of model transformations. However, it is challenging and error prone to debug them, and the situation gets more critical as the size and complexity of model transformations grow, where manual debugging is no longer possible.

Spectrum-Based Fault Localization (SBFL) uses the results of test cases and their corresponding code coverage information to estimate the likelihood of each program component (e.g., statements) of being faulty. In this article we present an approach to apply SBFL for locating the faulty rules in model transformations. We evaluate the feasibility and accuracy of the approach by comparing the effectiveness of 18 different state-of-the-art SBFL techniques at locating faults in model transformations. Evaluation results revealed that the best techniques, namely
Kulcynski2
,
Mountford
,
Ochiai
, and
Zoltar
, lead the debugger to inspect a maximum of three rules to locate the bug in around 74% of the cases. Furthermore, we compare our approach with a static approach for fault localization in model transformations, observing a clear superiority of the proposed SBFL-based method.
Layer-Centric Memory Reuse and Data Migration for Extreme-Scale Deep Learning on Many-Core Architectures
Authors: Jin Hai , Liu Bo , Jiang Wenbin , Ma Yang , Shi Xuanhua , He Bingsheng , Zhao Shaofeng
Published: September 2018

Due to the popularity of Deep Neural Network (DNN) models, we have witnessed extreme-scale DNN models with the continued increase of the scale in terms of depth and width. However, the extremely high memory requirements for them make it difficult to run the training processes on single many-core architectures such as a Graphic Processing Unit (GPU), which compels researchers to use model parallelism over multiple GPUs to make it work. However, model parallelism always brings very heavy additional overhead. Therefore, running an extreme-scale model in a single GPU is urgently required. There still exist several challenges to reduce the memory footprint for extreme-scale deep learning. To address this tough problem, we first identify the memory usage characteristics for deep and wide convolutional networks, and demonstrate the opportunities for memory reuse at both the intra-layer and inter-layer levels. We then present Layrub, a runtime data placement strategy that orchestrates the execution of the training process. It achieves layer-centric reuse to reduce memory consumption for extreme-scale deep learning that could not previously be run on a single GPU. Experiments show that, compared to the original Caffe, Layrub can cut down the memory usage rate by an average of 58.2% and by up to 98.9%, at the moderate cost of 24.1% higher training execution time on average. Results also show that Layrub outperforms some popular deep learning systems such as GeePS, vDNN, MXNet, and Tensorflow. More importantly, Layrub can tackle extreme-scale deep learning tasks. For example, it makes an extra-deep ResNet with 1,517 layers that can be trained successfully in one GPU with 12GB memory, while other existing deep learning systems cannot.
Shape from Contour: Computation and Representation
Authors: Elder James H.
Published: September 2018

The human visual system reliably extracts shape information from complex natural scenes in spite of noise and fragmentation caused by clutter and occlusions. A fast, feedforward sweep through ventral stream involving mechanisms tuned for orientation, curvature, and local Gestalt principles produces partial shape representations sufficient for simpler discriminative tasks. More complete shape representations may involve recurrent processes that integrate local and global cues. While feedforward discriminative deep neural network models currently produce the best predictions of object selectivity in higher areas of the object pathway, a generative model may be required to account for all aspects of shape perception. Research suggests that a successful model will account for our acute sensitivity to four key perceptual dimensions of shape: topology, symmetry, composition, and deformation.
A Life in Vision
Authors: Dowling John E.
Published: September 2018

I was drawn into research in George Wald's laboratory at Harvard, where as an undergraduate and graduate student, I studied vitamin A deficiency and dark adaptation. A chance observation while an assistant professor at Harvard led to the major research of my career—to understand the functional organization of vertebrate retinas. I started with a retinal circuit analysis of the primate retina with Brian Boycott and intracellular retinal cell recordings in mudpuppies with Frank Werblin. Subsequent pharmacology studies with Berndt Ehinger primarily with fish focused on dopamine and neuromodulation. Using zebrafish, we studied retinal development, neuronal connectivity, and the effects of genetic mutations on retinal structure and function. Now semi-retired, I have returned to primate retinal circuitry, undertaking a connectomic analysis of the human fovea in Jeffrey Lichtman's laboratory.
Glycoprotein nmb Is Exposed on the Surface of Dormant Breast Cancer Cells and Induces Stem Cell–like Properties
Authors: Chen Chen , Okita Yukari , Watanabe Yukihide , Abe Fumie , Fikry Muhammad Ali , Ichikawa Yumu , Suzuki Hiroyuki , Shibuya Akira , Kato Mitsuyasu
Published: September 2018

Glycoprotein nmb (GPNMB) is a type I transmembrane protein that contributes to the initiation and malignant progression of breast cancer through induction of epithelial–mesenchymal transition (EMT). Although it is known that EMT is associated with not only cancer invasion but also acquisition of cancer stem cell (CSC) properties, the function of GPNMB in this acquisition of CSC properties has yet to be elucidated. To address this issue, we utilized a three-dimensional (3D) sphere culture method to examine the correlation between GPNMB and CSC properties in breast cancer cells. Three-dimensional sphere cultures induced higher expression of CSC genes and EMT-inducing transcription factor (EMT-TF) genes than the 2D monolayer cultures. Three-dimensional culture also induced cell surface expression of GPNMB on limited numbers of cells in the spheres, whereas the 2D cultures did not. Therefore, we isolated cell surface-GPNMBhigh and -GPNMBlow cells from the spheres. Cell surface-GPNMBhigh cells expressed high levels of CSC genes and EMT-TF genes, had significantly higher sphere-forming frequencies than the cell surface-GPNMBlow cells, and showed no detectable levels of proliferation marker genes. Similar results were obtained from transplanted breast tumors. Furthermore, wild-type GPNMB, but not mutant GPNMB (YF), which lacks tumorigenic activity, induced CSC-like properties in breast epithelial cells. These findings suggest that GPNMB is exposed on the surface of dormant breast cancer cells and its activity contributes to the acquisition of stem cell–like properties.

Significance: These findings suggest that cell surface expression of GPNMB could serve as a marker and promising therapeutic target of breast cancer cells with stem cell-like properties. Cancer Res; 78(22); 6424–35. ©2018 AACR.
Evaluation of Explant Responses to STING Ligands: Personalized Immunosurgical Therapy for Head and Neck Squamous Cell Carcinoma
Authors: Baird Jason R. , Bell R. Bryan , Troesch Victoria , Friedman David , Bambina Shelly , Kramer Gwen , Blair Tiffany C. , Medler Terry , Wu Yaping , Sun Zhaoyu , de Gruijl Tanja D. , van de Ven Rieneke , Leidner Rom S. , Crittenden Marka R. , Gough Michael J.
Published: September 2018

Surgeons have unique in situ access to tumors enabling them to apply immunotherapies to resection margins as a means to prevent local recurrence. Here, we developed a surgical approach to deliver stimulator of interferon genes (STING) ligands to the site of a purposeful partial tumor resection using a gel-based biomaterial. In a range of head and neck squamous cell carcinoma (HNSCC) murine tumor models, we demonstrate that although control-treated tumors recur locally, tumors treated with STING-loaded biomaterials are cured. The mechanism of tumor control required activation of STING and induction of type I IFN in host cells, not cancer cells, and resulted in CD8 T-cell–mediated cure of residual cancer cells. In addition, we used a novel tumor explant assay to screen individual murine and human HNSCC tumor responses to therapies ex vivo. We then utilized this information to personalize the biomaterial and immunotherapy applied to previously unresponsive tumors in mice. These data demonstrate that explant assays identify the diversity of tumor-specific responses to STING ligands and establish the utility of the explant assay to personalize immunotherapies according to the local response.

Significance: Delivery of immunotherapy directly to resection sites via a gel-based biomaterial prevents locoregional recurrence of head and neck squamous cell carcinoma. Cancer Res; 78(21); 6308–19. ©2018 AACR.
Epigenetic Therapy with Panobinostat Combined with Bicalutamide Rechallenge in Castration-Resistant Prostate Cancer
Authors: Ferrari Anna C. , Alumkal Joshi J. , Stein Mark N. , Taplin Mary-Ellen , Babb James , Barnett Ethan S. , Gomez-Pinillos Alejandro , Liu Xiaomei , Moore Dirk , DiPaola Robert , Beer Tomasz M.
Published: September 2018

Purpose:

This study assesses the action of panobinostat, a histone deacetylase inhibitor (HDACI), in restoring sensitivity to bicalutamide in a castration-resistant prostate cancer (CRPC) model and the efficacy and safety of the panobinostat/bicalutamide combination in CRPC patients resistant to second-line antiandrogen therapy (2ndLAARx).

Patients and Methods:

The CWR22PC xenograft and isogenic cell line were tested for drug interactions on tumor cell growth and on the androgen receptor (AR), AR-splice variant7, and AR targets. A phase I trial had a 3 × 3 panobinostat dose-escalation design. The phase II study randomized 55 patients to panobinostat 40 mg (A arm) or 20 mg (B arm) triweekly ×2 weeks with bicalutamide 50 mg/day in 3-week cycles. The primary endpoint was to determine the percentage of radiographic progression-free (rPF) patients at 36 weeks versus historic high-dose bicalutamide.

Results:

In the model, panobinostat/bicalutamide demonstrated synergistic antitumor effect while reducing AR activity. The dose-limiting toxicity was not reached. The probabilities of remaining rPF were 47.5% in the A arm and 38.5% in the B arm, exceeding the protocol-specified threshold of 35%. The A arm but not the B arm exceeded expectations for times (medians) to rP (33.9 and 10 weeks), and from PSA progression to rP (24 and 5.9 weeks). A arm/B arm events included: adverse events (AE), 62%/19%; treatment stopped for AEs, 27.5%/11.5%; dose reduction required, 41%/4%. The principal A-arm grade ≥ 3 AEs were thrombocytopenia (31%) and fatigue (14%).

Conclusions:

The 40 mg panobinostat/bicalutamide regimen increased rPF survival in CRPC patients resistant to 2ndLAARx. Panobinostat toxicity was tolerable with dose reductions. Epigenetic HDACI therapy reduces AR-mediated resistance to bicalutamide in CRPC models with clinical benefit in patients. The combination merits validation using a second-generation antiandrogen.
The Anatomical Location Shapes the Immune Infiltrate in Tumors of Same Etiology and Affects Survival
Authors: Santegoets Saskia J. , van Ham Vanessa J. , Ehsan Ilina , Charoentong Pornpimol , Duurland Chantal L. , van Unen Vincent , Höllt Thomas , van der Velden Lilly-Ann , van Egmond Sylvia L. , Kortekaas Kim E. , de Vos van Steenwijk Peggy J. , van Poelgeest Mariëtte I.E. , Welters Marij J.P. , van der Burg Sjoerd H.
Published: September 2018

Purpose:

The tumor immune microenvironment determines clinical outcome. Whether the original tissue in which a primary tumor develops influences this microenvironment is not well understood.

Experimental Design:

We applied high-dimensional single-cell mass cytometry [Cytometry by Time-Of-Flight (CyTOF)] analysis and functional studies to analyze immune cell populations in human papillomavirus (HPV)–induced primary tumors of the cervix (cervical carcinoma) and oropharynx (oropharyngeal squamous cell carcinoma, OPSCC).

Results:

Despite the same etiology of these tumors, the composition and functionality of their lymphocytic infiltrate substantially differed. Cervical carcinoma displayed a 3-fold lower CD4:CD8 ratio and contained more activated CD8+CD103+CD161+ effector T cells and less CD4+CD161+ effector memory T cells than OPSCC. CD161+ effector cells produced the highest cytokine levels among tumor-specific T cells. Differences in CD4+ T-cell infiltration between cervical carcinoma and OPSCC were reflected in the detection rate of intratumoral HPV-specific CD4+ T cells and in their impact on OPSCC and cervical carcinoma survival. The peripheral blood mononuclear cell composition of these patients, however, was similar.

Conclusions:

The tissue of origin significantly affects the overall shape of the immune infiltrate in primary tumors.
Targeting Peroxisome Proliferator-Activated Receptor γ to Increase Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells
Authors: Fan Ping , Abderrahman Balkees , Chai Tina S. , Yerrum Smitha , Jordan V. Craig
Published: September 2018

Peroxisome proliferator-activated receptor γ (PPARγ) is an important transcription factor that modulates lipid metabolism and inflammation. However, it remains unclear whether PPARγ is involved in modulation of estrogen (E2)-induced inflammation, thus affecting apoptosis of E2-deprived breast cancer cells, MCF-7:5C and MCF-7:2A. Here, we demonstrated that E2 treatment suppressed the function of PPARγ in both cell lines, although the suppressive effect in MCF-7:2A cells was delayed owing to high PPARγ expression. Activation of PPARγ by a specific agonist, pioglitazone, selectively blocked the induction of TNFα expression by E2, but did not affect other adipose inflammatory genes, such as fatty acid desaturase 1 and IL6. This suppression of TNFα expression by pioglitazone was mainly mediated by transrepression of nuclear factor-κB (NF-κB) DNA-binding activity. A novel finding was that NF-κB functions as an oxidative stress inducer in MCF-7:5C cells but an antioxidant in MCF-7:2A cells. Therefore, the NF-κB inhibitor JSH-23 displayed effects equivalent to those of pioglitazone, with complete inhibition of apoptosis in MCF-7:5C cells, but it increased E2-induced apoptosis in MCF-7:2A cells. Depletion of PPARγ by siRNA or the PPARγ antagonist T0070907 accelerated E2-induced apoptosis, with activation of NF-κB–dependent TNFα and oxidative stress. For the first time, we demonstrated that PPARγ is a growth signal and has potential to modulate NF-κB activity and oxidative stress in E2-deprived breast cancer cell lines. All of these findings suggest that anti-PPARγ therapy is a novel strategy to improve the therapeutic effects of E2-induced apoptosis in E2-deprived breast cancer.
Impact of KDIGO-Defined Acute Kidney Injury on Mortality after Percutaneous Coronary Intervention for Acute Myocardial Infarction
Authors: Kanic Vojko , Kompara Gregor , Suran David , Ekart Robert , Bevc Sebastjan , Hojs Radovan
Published: September 2018

Background: There are limited data regarding the incidence and long-term impact of acute kidney injury (AKI) according to the KDIGO guidelines on the outcome in patients with myocardial infarction (MI) treated with percutaneous coronary intervention (PCI). The aim of the study was to evaluate the prevalence of AKI, as classified by the KDIGO criteria, and its association with long-term mortality. Methods: Data from 5,859 MI patients undergoing PCI at our institution were analyzed. We compared the group without and with AKI according to the KDIGO criteria in relation to long-term mortality. Results: AKI was documented in 499 (8.5%) patients. AKI stage 1 occurred in 6.2% of patients, AKI stage 2 in 0.9% of patients, and AKI stage 3 in 1.5% of patients. Patients with AKI had a higher long-term mortality (57.3 vs. 20.6%; p < 0.0001). The mortality was 50.3% in AKI stage 1, 56.9% in AKI stage 2, and 87.2% in AKI stage 3. The hazard ratios for all-cause mortality for AKI stages 1–3 were 1.77, 1.85, and 6.30 compared to patients with no AKI. Cardiogenic shock, bleeding, heart failure, age, renal dysfunction, diabetes, hyperlipidemia, ST-elevation MI, contrast volume/glomerular filtration ratio, P2Y12 receptor antagonists, and radial access were associated with the development of AKI. Conclusion: A slight increase in serum creatinine was associated with a progressive increase in long-term mortality in patients with AKI according to the KDIGO definition.
The Role of Nutrition and the Gut-Brain Axis in Psychiatry: A Review of the Literature
Authors: Mörkl Sabrina , Wagner-Skacel Jolana , Lahousen Theresa , Lackner Sonja , Holasek Sandra Johanna , Bengesser Susanne Astrid , Painold Annamaria , Holl Anna Katharina , Reininghaus Eva 
Published: September 2018

Introduction: Individuals suffering from psychiatric disorders experience high levels of illness burden and a significantly reduced quality of life. Despite targeted psychopharmacological strategies and complementary psychotherapeutic procedures only moderate effects are obtained, and the risk of relapse is high in many patients. Worldwide, psychiatric diseases such as depression are continuously increasing, challenging the personal life of the affected as well as their families, but also whole societies by increasing disability, early retirement and hospitalization. According to current scientific knowledge psychiatric disorders are caused by a multifactorial pathogenesis, including genetics, inflammation and neurotransmitter imbalance; furthermore, also lifestyle-associated factors gain rising importance. In line with this, there is growing evidence that the gut microbiota and nutrition have an impact on the onset and course of psychiatric disorders. Aim: This narrative review highlights the important role of nutrition in psychiatric care and underlines the significance of nutritional advice in the multifactorial, biopsychosocial treatment of patients. It focuses on current dietary interventions such as the Mediterranean diet, dietary supplements and modifications of the gut microbiota with pre-, pro- and postbiotics. Results: Recent studies support the connection between the quality of diet, gut microbiota and mental health through regulation of metabolic functions, anti-inflammatory and antiapoptotic properties and the support of neurogenesis. Dietary coaching to improve mental health seems to be an additional, cost-effective, practical, nonpharmacological intervention for individuals with psychiatric disorders. Conclusion: The use of nutritional interventions in psychiatry equips therapists with a promising tool for both the prevention and treatment of psychiatric disorders. Besides pharmacological therapy, psychotherapy and physical activity, nutritional interventions are an important pillar in the multifactorial, biopsychosocial treatment of psychiatric disease and could be used as a potential therapeutic target.
miR-184 Inhibits Tumor Invasion, Migration and Metastasis in Nasopharyngeal Carcinoma by Targeting Notch2
Authors: Zhu Hong-Ming , Jiang Xue-Song , Li Hui-Zi , Qian Lu-Xi , Du Ming-Yu , Lu Zhi-Wei , Wu Jing , Tian Xiao-Kang , Fei Qian , He Xia , Yin Li
Published: September 2018

Background/Aims: A recent study found that dysregulated microRNA-184 (miR-184) is involved in the proliferation and survival of nasopharyngeal carcinoma (NPC). This study aimed to evaluate the detailed mechanisms of invasion, migration and metastasis of NPC cells. Methods: Quantitative reverse-transcription PCR (qRT-PCR) and Western blot were used to confirm the expression levels of miR-184 and Notch2. NPC cell invasion and migration were subsequently examined using in vitro cell invasion and wound-healing assays, respectively. MicroRNA (miRNA) target gene prediction databases and dual-luciferase reporter assay were adopted to validate the target genes of miR-184. Results: MiR-184 was downregulated in the NPC cell lines. The miR-184 inhibitor increased the number of invading NPC cells, whereas miR-184 mimics inhibited the invasive ability of such cells. The protein level of E-cadherin decreased, whereas those of N-cadherin and vimentin increased in the anti-miR-184 group. This result showed that miR-184 inhibited NPC cell invasion and metastasis by regulating EMT progression. MiRNA target gene prediction databases indicated the potential of Notch2 as a direct target gene of miR-184. Such a notion was then validated by results of dual-luciferase reporter assay. Notably, shRNANotch2 restrained the EMT and partially abrogated the inhibitory effects of miR-184 on EMT progression in NPC cells. Conclusion: MiR-184 functions as a tumour-suppressive miRNA targeting Notch2 and inhibits the invasion, migration and metastasis of NPC.
Colorectal Neuroendocrine Neoplasms: Areas of Unmet Need
Authors: Ramage John K. , Valle Juan W. , Nieveen van Dijkum Els J.M. , Sundin Anders , Pascher Andreas , Couvelard Anne , Kloeppel Guenter ,   the ENETS 2016 Munich Advisory Board Participants
Published: September 2018

The subject of colorectal neuroendocrine neoplasms (NENs), subdivided into well-differentiated NENs, termed neuroendocrine tumours (NETs; grade (G) 1 and 2), and poorly differentiated NENs, termed neuroendocrine carcinomas (NECs; G3) according to the 2010 World Health Organisation (WHO) classification, has arguably not had as much attention or study as NENs occurring in other sites. Colorectal NETs and NECs are however easier to study than many others since they are usually not difficult to remove and are increasingly detected because of intensified colorectal cancer screening and surveillance programmes. Colorectal NETs and NECs show site-specific heterogeneity with variable behaviour and different therapeutic options; these various aspects provide unique challenges. Because of bowel cancer screening programmes, colorectal NENs, like conventional adenocarcinomas, may be diagnosed at a stage that is associated with improved survival. In this article we intend to describe and define areas of unmet needs relating to the epidemiology, classification, pathology, diagnosis and therapy of colorectal NETs (including NETs G3), colorectal NECs, and finally, mixed adeno-neuroendocrine carcinomas (MANECs) by reviewing and discussing the relevant literature.
Outcomes After Implantable Cardioverter-Defibrillator Generator Replacement for Primary Prevention of Sudden Cardiac Death
Authors: Madhavan Malini , Waks Jonathan W. , Friedman Paul A. , Kramer Daniel B. , Buxton Alfred E. , Noseworthy Peter A. , Mehta Ramila A. , Hodge David O. , Higgins Angela Y. , Webster Tracy L. , Witt Chance M. , Cha Yong-Mei , Gersh Bernard J.
Published: September 2018

Background—

The effectiveness of implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden death in patients with an ejection fraction (EF) ≤35% and clinical heart failure is well established. However, outcomes after replacement of the ICD generator in patients with recovery of EF to >35% and no previous therapies are not well characterized.

Methods and Results—

Between 2001 and 2011, generator replacement was performed at 2 tertiary medical centers in 253 patients (mean age, 68.3±12.7 years; 82% men) who had previously undergone ICD placement for primary prevention but subsequently never received appropriate ICD therapy. EF had recovered to >35% in 72 of 253 (28%) patients at generator replacement. During median (quartiles) follow-up of 3.3 (1.8–5.3) years after generator replacement, 68 of 253 (27%) experienced appropriate ICD therapy. Patients with EF ≤35% were more likely to experience ICD therapy compared with those with EF >35% (12% versus 5% per year; hazard ratio, 3.57;
P
=0.001). On multivariable analysis, low EF predicted appropriate ICD therapy after generator replacement (hazard ratio, 1.96 [1.35–2.87] per 10% decrement;
P
=0.001). Death occurred in 25% of patients 5 years after generator replacement. Mortality was similar in patients with EF ≤35% and >35% (7% versus 5% per year; hazard ratio, 1.10;
P
=0.68). Atrial fibrillation (3.24 [1.63–6.43];
P
<0.001) and higher blood urea nitrogen (1.28 [1.14–1.45] per increase of 10 mg/dL;
P
<0.001) were associated with mortality.

Conclusions—

Although approximately one fourth of patients with a primary prevention ICD and no previous therapy have EF >35% at the time of generator replacement, these patients continue to be at significant risk for appropriate ICD therapy (5% per year). These data may inform decisions on ICD replacement.
Patient, Provider, and Practice Characteristics Associated With Sacubitril/Valsartan Use in the United States
Authors: DeVore Adam D. , Hill C. Larry , Thomas Laine , Sharma Puza P. , Albert Nancy M. , Butler Javed , Patterson J. Herbert , Spertus John A. , Williams Fredonia B. , Duffy Carol I. , McCague Kevin , Hernandez Adrian F. , Fonarow Gregg C.
Published: September 2018

Background

Current guidelines recommend sacubitril/valsartan for patients with heart failure with reduced ejection fraction, but the rate of adoption in the United States has been slow.

Methods and Results

Using data from CHAMP-HF (Change the Management of Patients With Heart Failure), we described current sacubitril/valsartan use and identified patient, provider, and practice characteristics associated with its use. We considered patients to be on sacubitril/valsartan if they were prescribed it before enrollment or initiated on it at the baseline visit. We excluded patients with a contraindication to sacubitril/valsartan and practices with <10 patients enrolled. Of 4216 patients from 121 sites, 616 (15%) were prescribed sacubitril/valsartan, 2506 (59%) an angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), and 1094 (26%) neither. Patients prescribed sacubitril/valsartan were younger (63 years versus 66 years ACE inhibitor/ARB versus 69 years neither,
P
<0.001), less likely to have chronic kidney disease (15% versus 17% ACE inhibitor/ARB versus 30% neither,
P
<0.001), more likely to have cardiac resynchronization therapy (12% versus 7% ACE inhibitor/ARB versus 7% neither,
P
<0.001), and had lower ejection fraction (27% versus 30% ACE inhibitor/ARB versus 30% neither,
P
<0.001). Larger practices, based on number of cardiologists and advanced practice providers, were associated with the highest sacubitril/valsartan use. After multivariable adjustment, the number of advanced practice providers was associated with sacubitril/valsartan use (adjusted odds ratio,1.08; 95% CI, 1.03–1.14).

Conclusions

Despite current guideline recommendations, adoption of sacubitril/valsartan remains low. Provider and practice characteristics associated with sacubitril/valsartan use were related to general practice size and were not associated with practice characteristics specific for heart failure. Further research is needed to identify strategies for effective quality improvement interventions in chronic heart failure with reduced ejection fraction.
Regional Strain by Cardiac Magnetic Resonance Imaging Improves Detection of Right Ventricular Scar Compared With Late Gadolinium Enhancement on a Multimodality Scar Evaluation in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Zghaib Tarek , Ghasabeh Mounes Aliyari , Assis Fabrizio R. , Chrispin Jonathan , Keramati Ali , Misra Satish , Berger Ronald , Calkins Hugh , Kamel Ihab , Nazarian Saman , Zimmerman Stefan , Tandri Harikrishna
Published: September 2018

Background:

Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiomyopathy characterized by fibrofatty replacement of right ventricular myocardium resulting in reentrant ventricular tachycardia (VT). Cardiac magnetic resonance imaging (CMR) can noninvasively measure regional abnormalities using tissue-tracking strain as well as late gadolinium enhancement (LGE). In this study, we examine arrhythmogenic substrate using regional CMR strain, LGE, and electroanatomic mapping (EAM) in arrhythmogenic right ventricular cardiomyopathy patients presenting for VT ablation.

Methods and Results:

Twenty-one patients underwent right ventricular endocardial EAM, whereas 17 underwent epicardial EAM, to detect dense scar (<0.5 mV) as well as CMR study within 12 months. Quantitative regional strain analysis was performed in all 21 patients, although the presence of LGE was visually examined in 17 patients. Strain was lower in segments with dense scar on endocardial and epicardial EAM (−9.7±4.1 versus −7.3±4.0, and −9.8±2.8 versus −7.6±3.8;
P
<0.05), in segments with LGE scar (−9.9±4.4 versus −6.0±3.6;
P
=0.001), and at VT culprit sites (−7.4±3.7 versus −10.1±4.1;
P
<0.001), compared with the rest of right ventricular. On patient-clustered analysis, a unit increase in strain was associated with 21% and 18% decreased odds of scar on endocardial and epicardial EAM, respectively, 17% decreased odds of colocalizing VT culprit site, and 43% decreased odds of scar on LGE-CMR (
P
<0.05 for all). LGE and EAM demonstrated poor agreement with κ=0.18 (endocardial, n=17) and κ=0.06 (epicardial, n=13). Only 8 (15%) VT termination sites exhibited LGE.

Conclusions:

Regional myocardial strain on cine CMR improves detection of arrhythmogenic VT substrate compared with LGE. This may enhance diagnostic accuracy of CMR in arrhythmogenic right ventricular cardiomyopathy without the need for invasive procedures and facilitate the planning of VT ablation procedures.
Current Society of Thoracic Surgeons Model Reclassifies Mortality Risk in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Kumar Arnav , Sato Kimi , Narayanswami Jyoti , Banerjee Kinjal , Andress Krystof , Lokhande Chetan , Mohananey Divyanshu , Anumandla Anil Kumar , Khan Abdur Rahman , Sawant Abhishek C. , Menon Vivek , Krishnaswamy Amar , Tuzcu E. Murat , Jaber Wael A. , Mick Stephanie , Svensson Lars G. , Kapadia Samir R.
Published: September 2018

Background:

The Society of Thoracic Surgeons (STS) scores are used to screen patients for transcatheter aortic valve replacement (TAVR). The STS scores were also used to risk stratify patients in major TAVR trials. This study evaluates the reclassification of predicted risk of mortality by the currently available online STS score calculator compared with the 2008 STS risk model in patients undergoing TAVR.

Methods and Results:

All patients who underwent TAVR from 2006 to 2016 were included in the study. The STS scores for all included patients were calculated by applying the 2008 STS risk model and again using the current STS online calculator. Among 1209 patients who underwent TAVR, 30-day mortality was 27 (2.2%). The overall predicted risk of mortality estimated by using the current online STS risk calculator was significantly lower than the 2008 STS risk model (6.3±4.4 vs 7.3±4.9;
P
<0.001). A total of 235 (19%) patients were reclassified into a lower risk category per the current STS risk model. In a multivariable logistic regression analysis, patients with persistent atrial fibrillation (odds ratio, 1.4; 95% CI, 1.0–1.9;
P
=0.03), chronic heart failure (odds ratio, 6.0; 95% CI, 3.8–10.1;
P
<0.001), and New York Heart Association class IV heart failure (odds ratio, 2.4; 95% CI, 1.3–4.4;
P
=0.007) were more likely to be reclassified into a lower risk category per the current STS risk model.

Conclusions:

The current STS calculation method produces significantly lower predicted risk of mortality than the 2008 calculator, more pronounced in patients with certain comorbid conditions. These results should be considered while evaluating data from prior studies of TAVR.
Generation of Cardiomyocytes From Vascular Adventitia-Resident Stem Cells
Authors: Mekala Subba Rao , Wörsdörfer Philipp , Bauer Jochen , Stoll Olga , Wagner Nicole , Reeh Laurens , Loew Kornelia , Eckner Georg , Kwok Chee Keong , Wischmeyer Erhard , Dickinson Mary Eleanor , Schulze Harald , Stegner David , Benndorf Ralf A. , Edenhofer Frank , Pfeiffer Verena , Kuerten Stefanie , Frantz Stefan , Ergün Süleyman
Published: September 2018

Rationale:

Regeneration of lost cardiomyocytes is a fundamental unresolved problem leading to heart failure. Despite several strategies developed from intensive studies performed in the past decades, endogenous regeneration of heart tissue is still limited and presents a big challenge that needs to be overcome to serve as a successful therapeutic option for myocardial infarction.

Objective:

One of the essential prerequisites for cardiac regeneration is the identification of endogenous cardiomyocyte progenitors and their niche that can be targeted by new therapeutic approaches. In this context, we hypothesized that the vascular wall, which was shown to harbor different types of stem and progenitor cells, might serve as a source for cardiac progenitors.

Methods and Results:

We describe generation of spontaneously beating mouse aortic wall-derived cardiomyocytes without any genetic manipulation. Using aortic wall-derived cells (AoCs) of WT (wild type), αMHC (α-myosin heavy chain), and Flk1 (fetal liver kinase 1)-reporter mice and magnetic bead-associated cell sorting sorting of Flk1
+
AoCs from GFP (green fluorescent protein) mice, we identified Flk1
+
CD (cluster of differentiation) 34
+
Sca-1 (stem cell antigen-1)-CD44
−
AoCs as the population that gives rise to aortic wall-derived cardiomyocytes. This AoC subpopulation delivered also endothelial cells and macrophages with a particular accumulation within the aortic wall-derived cardiomyocyte containing colonies. In vivo, cardiomyocyte differentiation capacity was studied by implantation of fluorescently labeled AoCs into chick embryonic heart. These cells acquired cardiomyocyte-like phenotype as shown by αSRA (α-sarcomeric actinin) expression. Furthermore, coronary adventitial Flk1
+
and CD34
+
cells proliferated, migrated into the myocardium after mouse myocardial infarction, and expressed Isl-1
+
(insulin gene enhancer protein-1) indicative of cardiovascular progenitor potential.

Conclusions:

Our data suggest Flk1
+
CD34
+
vascular adventitia-resident stem cells, including those of coronary adventitia, as a novel endogenous source for generating cardiomyocytes. This process is essentially supported by endothelial cells and macrophages. In summary, the therapeutic manipulation of coronary adventitia-resident cardiac stem and their supportive cells may open new avenues for promoting cardiac regeneration and repair after myocardial infarction and for preventing heart failure.
miR-146a Suppresses SUMO1 Expression and Induces Cardiac Dysfunction in Maladaptive Hypertrophy
Authors: Oh Jae Gyun , Watanabe Shin , Lee Ahyoung , Gorski Przemek A. , Lee Philyoung , Jeong Dongtak , Liang Lifan , Liang Yaxuan , Baccarini Alessia , Sahoo Susmita , Brown Brian D. , Hajjar Roger J. , Kho Changwon
Published: September 2018

Rationale:

Abnormal SUMOylation has emerged as a characteristic of heart failure (HF) pathology. Previously, we found reduced SUMO1 (small ubiquitin-like modifier 1) expression and SERCA2a (sarcoplasmic reticulum Ca
2+
-ATPase) SUMOylation in human and animal HF models. SUMO1 gene delivery or small molecule activation of SUMOylation restored SERCA2a SUMOylation and cardiac function in HF models. Despite the critical role of SUMO1 in HF, the regulatory mechanisms underlying SUMO1 expression are largely unknown.

Objective:

To examine miR-146a–mediated SUMO1 regulation and its consequent effects on cardiac morphology and function.

Methods and Results:

In this study, miR-146a was identified as a SUMO1-targeting microRNA in the heart. A strong correlation was observed between miR-146a and SUMO1 expression in failing mouse and human hearts. miR-146a was manipulated in cardiomyocytes through AAV9 (adeno-associated virus serotype 9)-mediated gene delivery, and cardiac morphology and function were analyzed by echocardiography and hemodynamics. Overexpression of miR-146a reduced SUMO1 expression, SERCA2a SUMOylation, and cardiac contractility in vitro and in vivo. The effects of miR-146a inhibition on HF pathophysiology were examined by transducing a tough decoy of miR-146a into mice subjected to transverse aortic constriction. miR-146a inhibition improved cardiac contractile function and normalized SUMO1 expression. The regulatory mechanisms of miR-146a upregulation were elucidated by examining the major miR-146a–producing cell types and transfer mechanisms. Notably, transdifferentiation of fibroblasts triggered miR-146a overexpression and secretion through extracellular vesicles, and the extracellular vesicle–associated miR-146a transfer was identified as the causative mechanism of miR-146a upregulation in failing cardiomyocytes. Finally, extracellular vesicles isolated from failing hearts were shown to contain high levels of miR-146a and exerted negative effects on the SUMO1/SERCA2a signaling axis and hence cardiomyocyte contractility.

Conclusions:

Taken together, our results show that miR-146a is a novel regulator of the SUMOylation machinery in the heart, which can be targeted for therapeutic intervention.
Micronutrient Deficiency Independently Predicts Time to Event in Patients With Heart Failure
Authors: Lennie Terry A. , Andreae Christina , Rayens Mary Kay , Song Eun Kyeung , Dunbar Sandra B. , Pressler Susan J. , Heo Seongkum , Kim JinShil , Moser Debra K.
Published: September 2018

Background

Dietary micronutrient deficiencies have been shown to predict event‐free survival in other countries but have not been examined in patients with heart failure living in the United States. The purpose of this study was to determine whether number of dietary micronutrient deficiencies in patients with heart failure was associated with shorter event‐free survival, defined as a combined end point of all‐cause hospitalization and death.

Methods and Results

Four‐day food diaries were collected from 246 patients with heart failure (age: 61.5±12 years; 67% male; 73% white; 45% New York Heart Association [NYHA] class
III
/
IV
) and analyzed using Nutrition Data Systems for Research. Micronutrient deficiencies were determined according to methods recommended by the Institute of Medicine. Patients were followed for 1 year to collect data on all‐cause hospitalization or death. Patients were divided according to number of dietary micronutrient deficiencies at a cut point of ≥7 for the
high deficiency
category versus <7 for the
no to moderate deficiency
category. In the full sample, 29.8% of patients experienced hospitalization or death during the year, including 44.3% in the high‐deficiency group and 25.1% in the no/moderate group. The difference in survival distribution was significant (log rank,
P
=0.0065). In a Cox regression, micronutrient deficiency category predicted time to event with depression,
NYHA
classification, comorbidity burden, body mass index, calorie and sodium intake, and prescribed angiotensin‐converting enzyme inhibitors, diuretics, or β‐blockers included as covariates.

Conclusions

This study provides additional convincing evidence that diet quality of patients with heart failure plays an important role in heart failure outcomes.
Clinical Significance of Get With the Guidelines–Heart Failure Risk Score in Patients With Chronic Heart Failure After Hospitalization
Authors: Suzuki Satoshi , Yoshihisa Akiomi , Sato Yu , Kanno Yuki , Watanabe Shunsuke , Abe Satoshi , Sato Takamasa , Oikawa Masayoshi , Kobayashi Atsushi , Yamaki Takayoshi , Kunii Hiroyuki , Nakazato Kazuhiko , Ishida Takafumi , Takeishi Yasuchika
Published: September 2018

Background

The Get With the Guidelines–Heart Failure (
GWTG
‐
HF
) risk score was developed using American Heart Association
GWTG
‐
HF
program data and predicts in‐hospital mortality in patients with acute heart failure (HF). We aimed to clarify the prognostic impacts of the
GWTG
‐
HF
risk score in patients with HF after discharge.

Methods and Results

We examined the
GWTG
‐
HF
score in 1452 patients with HF, who were admitted to our hospital and discharged after treatment, by calculating 7 predetermined variables. We divided all subjects into 3 groups according to the
GWTG
‐
HF
risk score (low, moderate, and high score groups). The plasma B‐type natriuretic peptide level significantly increased with increasing
GWTG
‐
HF
risk score severity (median values of B‐type natriuretic peptide: 167.0 in low, 260.7 in moderate, and 418.2 pg/mL in high score groups). We followed up all subjects after discharge, and there were 347 (23.9%) all‐cause deaths and 407 (28.0%) cardiac events in follow‐up periods. A Kaplan‐Meier survival curve demonstrated that event rates of all‐cause death and cardiovascular events, including worsening
HF
and cardiac death, significantly increased with increasing
GWTG
‐
HF
risk score severity in all subjects, and also in 749 patients with HF with preserved ejection fraction (ejection fraction ≥50%) and 703 patients with HF with reduced ejection fraction (ejection fraction <50%) patients. The multivariable Cox proportional hazard regression analysis demonstrated that the
GWTG
‐
HF
risk score was one of the significant predictors of all‐cause mortality and cardiac events (all‐cause mortality: hazard ratio, 1.537, 95% confidence interval, 1.172–2.023; cardiac events: hazard ratio, 1.584, 95% confidence interval, 1.344–1.860, per 10‐point increase of
GWTG
‐
HF
score).

Conclusions

The
GWTG
‐
HF
risk score is a useful multivariable score model for several years after hospitalization in patients with HF in a Japanese population.
Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability
Authors: Vila Cuenca Marc , Ferrantelli Evelina , Meinster Elisa , Pouw Stephan M. , Kovačević Igor , de Menezes Renee X. , Niessen Hans W. , Beelen Robert H.J. , Hordijk Peter L. , Vervloet Marc G.
Published: September 2018

Background

Dysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease (
CKD
). Supplementation with active vitamin D has been proposed to have vasoprotective potential in
CKD
, not only by direct effects on the endothelium but also by an increment of α‐Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia‐induced endothelial damage and the extent to which this was dependent on increased α‐Klotho concentrations.

Methods and Results

In a combined rat model of
CKD
with vitamin D deficiency, renal failure induced vascular permeability and endothelial‐gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α‐Klotho was found in the
CKD
model, which was not restored by paricalcitol. By measuring the real‐time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro‐permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial‐cadherin–based cell‐cell junctions and diminished F‐actin stress fiber organization, preventing the formation of endothelial intracellular gaps.

Conclusions

Our results demonstrate that paricalcitol attenuates the
CKD
‐induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell‐cell interactions.
Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy
Authors: Frustaci Andrea , Verardo Romina , Grande Claudia , Galea Nicola , Piselli Pierluca , Carbone Iacopo , Alfarano Maria , Russo Matteo Antonio , Chimenti Cristina
Published: September 2018

Background

Glycosphingolipid accumulation in Fabry cells generates a proinflammatory response that may influence disease evolution and responsiveness to enzyme replacement therapy. This study evaluated incidence, mechanism, and impact of myocarditis in Fabry disease cardiomyopathy (
FDCM
).

Methods and Results

Myocarditis, defined as
CD
3
+
T lymphocytes >7/mm
2
associated with necrosis of glycolipid‐laden myocardiocytes, was retrospectively evaluated in endomyocardial biopsies from 78 patients with
FDCM
: 13 with maximal wall thickness (MWT) <11 mm (group 1), 17 with MWT 11 to 15 mm (group 2), 30 with MWT 16 to 20 mm (group 3), and 18 with MWT >20 mm (group 4). Myocarditis was investigated by polymerase chain reaction for cardiotropic viruses, by serum antiheart and antimyosin antibodies, and by cardiac magnetic resonance. Myocarditis was recognized at histology in 48 of 78 patients with
FDCM
(38% of group 1, 41% of group 2, 66% of group 3, and 72% of group 4). Myocarditis was characterized by positive antiheart and antimyosin antibodies and negative polymerase chain reaction for viral genomes.
CD
3
+
cells/mm
2
correlated with myocyte necrosis, antimyosin autoantibody titer, and
MWT
(
P
<0.001,
r
=0.79;
P
<0.001,
r
=0.84;
P
<0.001,
r
=0.61, respectively). Cardiac magnetic resonance showed myocardial edema in 24 of 78 patients (31%): 0% of group 1, 23% of group 2, 37% of group 3, and 50% of group 4.

Conclusions

Myocarditis is detectable at histology in up to 56% of patients with
FDCM
. It is immune mediated and correlates with disease severity. It can be disclosed by antiheart/antimyosin autoantibodies and in the advanced phase by cardiac magnetic resonance. It may contribute to progression of
FDCM
and resistance to enzyme replacement therapy.
Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus
Authors: Bretón‐Romero Rosa , Weisbrod Robert M. , Feng Bihua , Holbrook Monika , Ko Darae , Stathos Mary M. , Zhang Ji‐Yao , Fetterman Jessica L. , Hamburg Naomi M.
Published: September 2018

Background

Prior studies have shown that nutrient excess induces endoplasmic reticulum (
ER
) stress in nonvascular tissues from patients with diabetes mellitus (
DM
).
ER
stress and the subsequent unfolded protein response may be protective, but sustained activation may drive vascular injury. Whether
ER
stress contributes to endothelial dysfunction in patients with DM remains unknown.

Methods and Results

To characterize vascular
ER
stress, we isolated endothelial cells from 42 patients with
DM
and 37 subjects without DM. Endothelial cells from patients with
DM
displayed higher levels of
ER
stress markers compared with controls without DM. Both the early adaptive response, evidenced by higher phosphorylated protein kinase–like ER eukaryotic initiation factor‐2a kinase and inositol‐requiring ER‐to‐nucleus signaling protein 1 (
P
=0.02,
P
=0.007, respectively), and the chronic
ER
stress response evidenced by higher C/
EBP
α‐homologous protein (
P
=0.02), were activated in patients with
DM
. Higher inositol‐requiring ER‐to‐nucleus signaling protein 1 activation was associated with lower flow–mediated dilation, consistent with endothelial dysfunction (
r
=0.53,
P
=0.02). Acute treatment with liraglutide, a glucagon‐like peptide 1 receptor agonist, reduced p‐inositol‐requiring ER‐to‐nucleus signaling protein 1 (
P
=0.01), and the activation of its downstream target c‐jun N‐terminal kinase (
P
=0.025) in endothelial cells from patients with
DM
. Furthermore, liraglutide restored insulin‐stimulated endothelial nitric oxide synthase activation in patients with
DM
(
P
=0.019).

Conclusions

In summary, our data suggest that
ER
stress contributes to vascular insulin resistance and endothelial dysfunction in patients with
DM
. Further, we have demonstrated that liraglutide ameliorates
ER
stress, decreases c‐jun N‐terminal kinase activation and restores insulin‐mediated endothelial nitric oxide synthase activation in endothelial cells from patients with
DM
.