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      Cardiovascular calcification: artificial intelligence and big data accelerate mechanistic discovery

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      Nature Reviews Cardiology
      Springer Nature

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          Abstract

          Cardiovascular calcification is a health disorder with increasing prevalence and high morbidity and mortality. The only available therapeutic options for calcific vascular and valvular heart disease are invasive transcatheter procedures or surgeries that do not fully address the wide spectrum of these conditions; therefore, an urgent need exists for medical options. Cardiovascular calcification is an active process, which provides a potential opportunity for effective therapeutic targeting. Numerous biological processes are involved in calcific disease, including matrix remodelling, transcriptional regulation, mitochondrial dysfunction, oxidative stress, calcium and phosphate signalling, endoplasmic reticulum stress, lipid and mineral metabolism, autophagy, inflammation, apoptosis, loss of mineralization inhibition, impaired mineral resorption, cellular senescence and extracellular vesicles that act as precursors of microcalcification. Advances in molecular imaging and big data technology, including in multiomics and network medicine, and the integration of these approaches are helping to provide a more comprehensive map of human disease. In this Review, we discuss ectopic calcification processes in the cardiovascular system, with an emphasis on emerging mechanistic knowledge obtained through patient data and advances in imaging methods, experimental models and multiomics-generated big data. We also highlight the potential and challenges of artificial intelligence, machine learning and deep learning to integrate imaging and mechanistic data for drug discovery.

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          Most cited references127

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          Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation

          Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.
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            Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals.

            Guidelines advise that all adults undergo coronary heart disease (CHD) risk assessment to guide preventive treatment intensity. Although the Framingham Risk Score (FRS) is often recommended for this, it has been suggested that risk assessment may be improved by additional tests such as coronary artery calcium scoring (CACS). To determine whether CACS assessment combined with FRS in asymptomatic adults provides prognostic information superior to either method alone and whether the combined approach can more accurately guide primary preventive strategies in patients with CHD risk factors. Prospective observational population-based study, of 1461 asymptomatic adults with coronary risk factors. Participants with at least 1 coronary risk factor (>45 years) underwent computed tomography (CT) examination, were screened between 1990-1992, were contacted yearly for up to 8.5 years after CT scan, and were assessed for CHD. This analysis included 1312 participants with CACS results; excluded were 269 participants with diabetes and 14 participants with either missing data or had a coronary event before CACS was performed. Nonfatal myocardial infarction (MI) or CHD death. During a median of 7.0 years of follow-up, 84 patients experienced MI or CHD death; 70 patients died of any cause. There were 291 (28%) participants with an FRS of more than 20% and 221 (21%) with a CACS of more than 300. Compared with an FRS of less than 10%, an FRS of more than 20% predicted the risk of MI or CHD death (hazard ratio [HR], 14.3; 95% confidence interval [CI]; 2.0-104; P =.009). Compared with a CACS of zero, a CACS of more than 300 was predictive (HR, 3.9; 95% CI, 2.1-7.3; P<.001). Across categories of FRS, CACS was predictive of risk among patients with an FRS higher than 10% (P<.001) but not with an FRS less than 10%. These data support the hypothesis that high CACS can modify predicted risk obtained from FRS alone, especially among patients in the intermediate-risk category in whom clinical decision making is most uncertain.
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              Phosphate regulation of vascular smooth muscle cell calcification.

              Vascular calcification is a common finding in atherosclerosis and a serious problem in diabetic and uremic patients. Because of the correlation of hyperphosphatemia and vascular calcification, the ability of extracellular inorganic phosphate levels to regulate human aortic smooth muscle cell (HSMC) culture mineralization in vitro was examined. HSMCs cultured in media containing normal physiological levels of inorganic phosphate (1.4 mmol/L) did not mineralize. In contrast, HSMCs cultured in media containing phosphate levels comparable to those seen in hyperphosphatemic individuals (>1.4 mmol/L) showed dose-dependent increases in mineral deposition. Mechanistic studies revealed that elevated phosphate treatment of HSMCs also enhanced the expression of the osteoblastic differentiation markers osteocalcin and Cbfa-1. The effects of elevated phosphate on HSMCs were mediated by a sodium-dependent phosphate cotransporter (NPC), as indicated by the ability of the specific NPC inhibitor phosphonoformic acid, to dose dependently inhibit phosphate-induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. With the use of polymerase chain reaction and Northern blot analyses, the NPC in HSMCs was identified as Pit-1 (Glvr-1), a member of the novel type III NPCs. These data suggest that elevated phosphate may directly stimulate HSMCs to undergo phenotypic changes that predispose to calcification and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. The full text of this article is available at http://www.circresaha.org.
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                Author and article information

                Journal
                Nature Reviews Cardiology
                Nat Rev Cardiol
                Springer Nature
                1759-5002
                1759-5010
                December 10 2018
                Article
                10.1038/s41569-018-0123-8
                30531869
                f10c27ff-3966-419a-a1b7-648c6ab6df7f
                © 2018

                http://www.springer.com/tdm

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