bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imaging of microvascular disease
Authors: Camici Paolo G. , Rimoldi Ornella 
Published: June 2021

Abstract
Beside obstructive disease of the epicardial coronary arteries dysfunction of the coronary microvasculature has emerged in the past 20 years as an additional mechanism of myocardial ischaemia. The coronary microvasculature cannot be directly visualized in vivo, therefore, both invasive and non-invasive techniques, have been developed to assess parameters that depend directly on coronary microvascular function. Studies at the microcirculatory level entail the use of vasodilators to obtain near-maximal vasodilation. The ratio of the maximal increase of blood flow above its resting value the coronary flow reserve (CFR) allows to gain an insight into the integrated circulatory function. The diagnostic accuracy of imaging techniques can be exploited to detect impairments of myocardial perfusion in asymptomatic subjects with cardiovascular risk factors. The assessment of the coronary microvascular function has provided novel details on the pathophysiological role of coronary microvascular dysfunction in the development of myocardial ischaemia bearing also important prognostic implications.
Evaluation of left ventricular diastolic function
Authors: Popescu Bogdan A. , Beladan Carmen C. , Galderisi Maurizio 
Published: June 2021

Abstract
This chapter looks at how left ventricular diastolic dysfunction (LVDD) is a key player in the pathophysiology of heart failure and it has prognostic implications even in the preclinical stage. Echocardiography is the first-line imaging modality used for the clinical evaluation of left ventricular (LV) diastolic function. A large number of echocardiographic parameters have been tested and validated against invasive measurements of diastolic function, each of them having potential limitations. The updated 2016 American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) recommendations proposed a comprehensive integrated approach aiming to make the assessment of LV diastolic function easier and accurate for daily clinical practice.
Imaging cardiac innervation
Authors: Flotats Albert , Carrió Ignasi 
Published: June 2021

Abstract
Cardiac autonomic nervous system contributes to maintain haemodynamic and electrophysiological stability to changing demands. Cardiac innervation imaging can be performed by means of planar scintigraphy/SPECT or PET using different radiotracers developed for the assessment of pre- and postsynaptic receptors of the cardiac autonomic nervous system, with sufficient sensitivity to assess a process that takes place at picomolar concentrations. Clinically, cardiac innervation imaging is mainly performed targeting postganglionic presynaptic sympathetic neurons by means of myocardial 123I-metaiodobenzylguanidine (123I-mIBG) planar scintigraphy and SPECT, which has shown to be of value in the assessment of patients with different cardiac disorders, especially in those with heart failure (HF), having an independent prognostic value. This clinically oriented chapter updates the subject with inclusion of new data reinforcing the use of sympathetic cardiac innervation imaging for improving patient management.
Cardiac resynchronization therapy: Optimization and follow-up
Authors: Sitges Marta , Donal Erwan 
Published: June 2021

Abstract
Cardiac imaging techniques have an important role in the follow-up of patients undergoing cardiac resynchronization therapy (CRT) as they provide objective evidence of changes in cardiac dimensions and function. The role of echocardiography is well established in the assessment of left ventricular reverse remodelling and the evaluation of secondary (functional) mitral regurgitation. Additionally, echocardiography might be used for optimizing the programming of atrioventricular (AV) and interventricular (VV) delays of current CRT devices. Acute benefit from this optimization has been demonstrated, but longer follow-up studies have failed to show a clear benefit of optimized CRT on top of simultaneous biventricular pacing on the outcome of patients with CRT. This chapter reviews the role of imaging in assessing follow-up and outcome of patients undergoing CRT as well as the rationale, the methods used, and the clinical impact of optimization of the programming of CRT devices.
Other genetic and acquired cardiomyopathies
Authors: Haugaa Kristina , Elliott Perry 
Published: June 2021

Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited, progressive cardiomyopathy associated with high risk of ventricular tachycardia associated with right-sided structural disorders. More recent reports have shown that although the right ventricle (RV) is most often affected, the left ventricle (LV) is also commonly involved. This has led to the more recent term arrhythmogenic cardiomyopathy (AC). Men are more frequently affected than women and it is usually diagnosed between the second and fourth decade of life. The most common presentation is ventricular arrhythmia, specifically ventricular tachycardia originating from the RV with a characteristic left bundle-branch block (LBBB) morphology. ARVC is also an important cause of sudden death in individuals &lt;30 years of age and has been found in up to 20% of sudden deaths in young individuals. Furthermore, ARVC is more common in athletes and disease expression is associated with high intensity exercise.
Myocarditis
Authors: Yilmaz Ali , Mahrholdt Heiko , Sechtem Udo 
Published: June 2021

Abstract
The symptoms and signs of myocarditis are non-specific. Thus, myocarditis is a differential diagnosis in many patients with heart complaints. As myocarditis may accompany common viral infections of the upper respiratory and gastrointestinal tracts, and mild ECG changes are not uncommon in such patients, the diagnosis needs to be considered in large patient cohorts. Establishing the correct diagnosis is of importance as the disease may lead to sudden cardiac death or dilated cardiomyopathy. As clinical tools such as history taking, physical examination, blood tests, the ECG, and the chest X-ray are not sufficient to ascertain the diagnosis of myocarditis, additional information from cardiac imaging techniques, or endomyocardial biopsy are necessary to confirm or exclude the disease. In daily clinical routine, however, the use of biopsy is limited to severely ill patients with reduced left ventricular function due to its invasiveness and potential complications. Thus, this chapter reviews how non-invasive cardiac imaging techniques can be used in clinical practice to diagnose myocarditis.
Aortic disease: Aneurysm and dissection—role of MSCT
Authors: Hinojar Rocío , Erbel Raimund 
Published: June 2021

Abstract
Multislice computed tomography (MSCT) is currently the preferred modality for diagnosis and complete characterization of aortic pathology because of its widespread availability, rapidity, excellent spatial resolution, and excellent accuracy for all aortic segments and different aortic diseases. Aortic disease often remains undiagnosed until a life-threatening complication occurs or the disease is an unexpected finding on imaging studies performed for other purposes. MSCT allows the measurement of the aortic wall and dimension and the evaluation of morphologic features and surrounding structures, even in very sick or unstable patients. It provides not only accurate and highly reproducible aortic measurements but also the evaluation of the wall and contents of an aneurysm, including thrombus, and surrounding structures.
The role of CMR and MSCT
Authors: Di Salvo Giovanni , Pluchinotta Francesca R. 
Published: June 2021

Abstract
Congenital heart disease (CHD) affects 6–8 per 1,000 of newborn infants. As a result of advances in cardiac surgery and clinical management, survival of patients with CHD has significantly improved over the last decades. Nowadays, it is estimated that 85% of children will survive to adulthood. Imaging is a crucial component to the multidisciplinary management of these patients. Techniques are required both to characterize anatomical structures and their functional status in order to improve management, evaluate the consequences of interventions, and help guide prognosis. Therefore, assessment for CHD requires a multimodality approach where a variety of imaging techniques should be used in a complementary fashion looking for sensitivity, accuracy, reproducibility, and cost-effectiveness, while minimizing harm to the patients.
Fast magnetoacoustic wave trains: from tadpoles to boomerangs
Authors: Kolotkov Dmitrii Y , Nakariakov Valery M , Moss Guy , Shellard Paul 
Published: June 2021

ABSTRACT
Rapidly propagating fast magnetoacoustic wave trains guided by field-aligned plasma non-uniformities are confidently observed in the Sun’s corona. Observations at large heights suggest that fast wave trains can travel long distances from the excitation locations. We study characteristic time signatures of fully developed, dispersive fast magnetoacoustic wave trains in field-aligned zero-β plasma slabs in the linear regime. Fast wave trains are excited by a spatially localized impulsive driver and propagate along the waveguide as prescribed by the waveguide-caused dispersion. In slabs with steeper transverse density profiles, developed wave trains are shown to consist of three distinct phases: a long-period quasi-periodic phase with the oscillation period shortening with time, a multiperiodic (peloton) phase in which distinctly different periods co-exist, and a short-lived periodic Airy phase. The appearance of these phases is attributed to a non-monotonic dependence of the fast wave group speed on the parallel wavenumber due to the waveguide dispersion, and is shown to be different for axisymmetric (sausage) and non-axisymmetric (kink) modes. In wavelet analysis, this corresponds to the transition from the previously known tadpole shape to a new boomerang shape of the wave train spectrum, with two well-pronounced arms at shorter and longer periods. We describe a specific previously published radio observation of a coronal fast wave train, highly suggestive of a change of the wavelet spectrum from a tadpole to a boomerang, broadly consistent with our modelling. The applicability of these boomerang-shaped fast wave trains for probing the transverse structuring of the waveguiding coronal plasma is discussed.
Formation and fate of the born-again planetary nebula HuBi 1
Authors: Toalá J A , Lora V , Montoro-Molina B , Guerrero M A , Esquivel A 
Published: June 2021

ABSTRACT
We present the first 3D radiation-hydrodynamic simulations on the formation and evolution of born-again planetary nebulae (PNe), with particular emphasis to the case of HuBi 1, the inside-out PN. We use the extensively tested guacho code to simulate the formation of HuBi 1 adopting mass-loss and stellar wind terminal velocity estimates obtained from observations presented by our group. We found that, if the inner shell of HuBi 1 was formed by an explosive very late thermal pulse (VLTP) ejecting material with velocities of ∼300 km s−1, the age of this structure is consistent with that of ≃200 yr derived from multi-epoch narrow-band imaging. Our simulations predict that, as a consequence of the dramatic reduction of the stellar wind velocity and photon ionizing flux during the VLTP, the velocity and pressure structure of the outer H-rich nebula are affected creating turbulent ionized structures surrounding the inner shell. These are indeed detected in Gran Telescopio Canarias MEGARA optical observations. Furthermore, we demonstrate that the current relatively low ionizing photon flux from the central star of HuBi 1 is not able to completely ionize the inner shell, which favours previous suggestions that its excitation is dominated by shocks. Our simulations suggest that the kinetic energy of the H-poor ejecta of HuBi 1 is at least 30 times that of the clumps and filaments in the evolved born-again PNe A 30 and A 78, making it a truly unique VLTP event.
The DEAD-box RNA helicase RhlE2 is a global regulator ofPseudomonas aeruginosalifestyle and pathogenesis
Authors: Hausmann Stéphane , Gonzalez Diego , Geiser Johan , Valentini Martina 
Published: June 2021

AbstractRNA helicases perform essential housekeeping and regulatory functions in all domains of life by binding and unwinding RNA molecules. The bacterial RhlE-like DEAD-box RNA helicases are among the least well studied of these enzymes. They are widespread especially among Proteobacteria, whose genomes often encode multiple homologs. The significance of the expansion and diversification of RhlE-like proteins for bacterial fitness has not yet been established. Here, we study the two RhlE homologs present in the opportunistic pathogen Pseudomonas aeruginosa. We show that, in the course of evolution, RhlE1 and RhlE2 have diverged in their biological functions, molecular partners and RNA-dependent enzymatic activities. Whereas RhlE1 is mainly needed for growth in the cold, RhlE2 also acts as global post-transcriptional regulator, affecting the level of hundreds of cellular transcripts indispensable for both environmental adaptation and virulence. The global impact of RhlE2 is mediated by its unique C-terminal extension, which supports the RNA unwinding activity of the N-terminal domain as well as an RNA-dependent interaction with the RNase E endonuclease and the cellular RNA degradation machinery. Overall, our work reveals how the functional and molecular divergence between two homologous RNA helicases can contribute to bacterial fitness and pathogenesis.
ATRT-01. IDENTIFICATION OF MICRORNA-BASED PROGNOSTIC BIOMARKERS AND CANDIDATE THERAPEUTIC AGENTS FOR ATYPICAL TERATOID/RHABDOID TUMOR
Authors: Zhang Yang 
Published: June 2021

Abstract

Background
MicroRNA (miRNA) has been found to be involved in development of many malignant pediatric brain tumors, including atypical teratoid/rhabdoid tumor (AT/RT) that is highly aggressive and carries a dismal prognosis. The current study investigated the potential value of miRNAs and pivotal genes associated with AT/RT using bioinformatics analysis, aiming to identify new prognostic biomarkers and candidate drugs for AT/RT patients.

Methods
Differentially expressed miRNAs (DEMs) and genes (DEGs) between AT/RT and normal control samples were obtained from GEO database. The target genes of DEMs were predicted via TargetScanHuman7.2 and miRDB, and then intersected with DEGs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of overlapping genes were conducted, followed by construction of protein-protein interaction network. Hub genes were determined by Cytoscape software, and their prognostic values were evaluated using Kaplan-Meier analysis. Connectivity Map database was used to identify latent therapeutic agents.

Results
A total of 11 DEMs (hsa-miR-1224-5p, hsa-miR-128-3p, hsa-miR-17-5p, hsa-miR-18b-5p, hsa-miR-29c-5p, hsa-miR-329-3p, hsa-miR-379-5p, hsa-miR-433-3p, hsa-miR-488-5p, hsa-miR-656-3p and hsa-miR-885-5p) were screened. By intersecting 3275 predicted target genes and 925 DEGs, we finally identified 226 overlapping genes that were enriched in pathways in cancer and MAPK signaling pathway. Four hub genes (GRIA2, NRXN1, SLC6A1 and SYT1) were significantly associated with the overall survival of AT/RT patients. Candidate drugs included histone deacetylase inhibitor (givinostat), DNA synthesis inhibitor (floxuridine), cyclin-dependent kinase inhibitor (purvalanol) and janus kinase inhibitor (lestaurtinib).

Conclusion
In summary, this study systematically analyzed AT/RT-related miRNAs and pivotal genes to provide novel prognostic biomarkers and potential therapeutic agents.
ATRT-02. THE DUAL MTORC1/2 INHIBITOR, TAK-228 COMBINES SYNERGISTICALLY WITH THE BH3 MIMETIC, OBATOCLAX TO IMPROVE SURVIVAL IN MICE BEARING ORTHOTOPIC XENOGRAFTS OF AT/RT
Authors: Findlay Tyler , Parkhurst Ashlyn , Wang Sabrina , Eberhart Charles , Raabe Eric , Rubens Jeffrey 
Published: June 2021

Abstract
mTOR activation drives tumorigenicity by regulating transcription factor expression and downstream growth and survival pathways. We have previously shown that mTORC1 and mTORC2 are highly activated in AT/RT and the dual mTORC1/2 inhibitor, TAK-228 (Sapanisertib) improves survival in mice bearing orthotopic xenografts of AT/RT. To design a rational combination therapy that enhances TAK-228’s efficacy and durability, we performed RNASeq 4 hours after TAK-228 treatment of AT/RT cell models. Pathway analysis revealed disruption of the NRF2-mediated stress response. NRF2 is a cap’n’collar leucine zipper transcription factor that regulates expression of genes involved in redox homeostasis, energy metabolism, cell proliferation, and survival. Analysis of publicly available RNASeq data on 32 human tumors identified elevated expression of NRF2 in AT/RT (median expression 40.78, normal brain 18.81). Short-hairpin knockdown of NRF2 decreased the expression of NRF2 as well as the anti-apoptotic proteins MCL-1, BCL-xL, and BCL-2 (western blot), and intracellular concentrations of reduced glutathione (p&lt;0.005, t-test). TAK-228 similarly decreased expression of NRF2, MCL-1, and glutathione (p&lt;0.005, t-test) demonstrating that TAK-228 compromises AT/RT defenses against oxidative stress and cell death. The brain-penetrant BH3 mimetic, Obatoclax increases oxidative stress and induces apoptosis in AT/RT (MUSE oxidative stress, cPARP western blot, t-test p&lt;0.05). These complementary mechanisms of action synergize to slow AT/RT cell growth (MUSE Cell viability assay, ANOVA p&lt;0.05) and induce high rates of cell death (MUSE ANNEXIN V assay, ANOVA p&lt;0.05, Western blot for cPARP, Compusyn Synergy analysis CI&lt;1.0). Once-weekly treatments of TAK-228 combined with Obatoclax in orthotopic mouse models of AT/RT is well tolerated, slows tumor growth (bioluminescence imaging, ANOVA p&lt;0.05) and significantly extends median survival from 35 to 55 days (Log-rank p&lt;0.05). These findings support a new clinical trial aimed at improving AT/RT survival.
BIOL-05. MAPK PATHWAY INHIBITION SENSITIZES TO IMMUNOTHERAPY IN BRAF-MUTANT GLIOMAS
Authors: Park Jong-Whi , Barrette Anne-Marie , Wang Wei , Grossauer Stefan , Grant Gerald , Lau Ken , Pitteri Sharon , Monje Michelle , Petritsch Claudia 
Published: June 2021

Abstract

Background
BRAF alterations frequently occur in pediatric low-grade gliomas. Previously, we showed that dabrafenib and trametinib (D+T) that target MAPK pathway can mediate the antitumor effect in a preclinical model of BRAF-mutant glioma (PMC5342782). Here, we further investigate the effect of MAPK pathway inhibitors on cancer cells and tumor-infiltrating immune cells to maximize the therapeutic efficacy in malignant gliomas.

Methods
Drug concentrations in tumor, brain and plasma were assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RNA sequencing and Gene Set Enrichment Analysis were performed using patient-derived BRAF-mutant glioma lines upon D+T treatment. Molecular profiles of drug-resistant clones were assessed for understanding of glioma heterogeneity and exploring new therapeutic targets. Results. BRAF-mutant stem-like glioma cells were particularly resistant to BRAF or MAPK inhibitor, along with aggressive phenotype in mice. LC-MS/MS showed effective D+T drug delivery in tumor regions. The transcriptome analysis demonstrated that D+T upregulate HLA molecules and downregulate immunosuppressive factors in patient-derived BRAF-mutant glioma lines. Consistent with these molecular changes, D+T led to changes in the proportions of tumor-infiltrating immune cells, including CD8+ cytotoxic T lymphocytes and FOXP3+ regulatory T cells. Furthermore, the therapeutic effect of D+T was further enhanced in combination with immune checkpoint inhibition.

Conclusions
The present study highlights the immunomodulatory activity of MAPK pathway inhibitors in BRAF-mutant gliomas.
EMBR-06. EFFECTIVE INHIBITION OF MYC-AMPLIFIFIED GROUP 3 MEDULLOBLASTOMA BY FACT-TARGETED CURAXIN DRUG CBL0137
Authors: Wang Jiajia , Ma Jie 
Published: June 2021

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor that can be categorized into four major molecular subgroups. Group 3 MB with MYC amplifification (MYCamp-G3-MB) has been shown to be highly aggressive and exhibited worst prognosis, indicating the need for novel effective therapy most urgently. A few epigenetic targeted therapeutic strategies have recently been proven to effectively treat preclinical models of MYCamp-G3-MB, including BET inhibition, HDAC inhibition and SETD8 inhibition, unveiling a promising direction for further investigation. In this study, we carried out systemic bioinformatic analyses of public-available MB datasets as well as functional genomic screening datasets of primary MYCamp-G3-MB lines to search for other potential therapeutic targets within epigenetic modulators. We identifified SSRP1, a subunit of histone-chaperone FACT complex, to be the top drug target candidate as it is highly cancer-dependent in whole-genome CRISPR-Cas9 screening across multiple MYCamp-G3-MB lines; signifificantly upregulated in MYCamp-G3-MB compared to normal cerebellum and most of the rest MB subtypes; its higher expression is correlated with worse prognosis; and it has a blood-brain-barrier penetrable targeted drug that has entered early phase human clinical trials already. Then we utilized RNA-interference approach to verify the cancer-dependency of SSRP1 in multiple MYCamp-G3-MB lines and further confifirmed the therapeutic effificacy of FACT-targeted curaxin drug CBL0137 on treating preclinical models of MYCamp-G3-MB in vitro and in vivo, including an orthotopic intracranial xenograft model. Mechanistically, transcriptome analyses showed CBL0137 preferentially suppressed cell-cycle and DNA-repair related biological processes. Moreover, it selectively disrupted transcription of MYC and NEUROD1, two critical oncogenic transcription factors of MYCamp-G3-MB, via depleting FACT complex from their promoter regions. In summary, our study demonstrates FACT-targeted CBL0137 works effectively on treating MYCamp-G3-MB, presenting another promising epigenetic-targeted therapeutic strategy against the most devastating form of MB.