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Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic, Mendelian disorders is amply demonstrated, clinical utility is less evident in polygenic traits, e.g., coronary artery disease or breast cancer. Polygenic risk scores (PRS) are subsets of individual genotypes designed to capture heritability of common traits, and hence to allow the stratification of risk of the trait in a population. We systematically reviewed the PubMed database for unequivocal evidence of clinical utility of polygenic risk scores, using stringent inclusion and exclusion criteria. While we identified studies demonstrating clinical validity in conditions where medical intervention based on a PRS is likely to benefit patient outcome, we did not identify a single study demonstrating unequivocally such a benefit, i.e. clinical utility. We conclude that while the routine use of PRSs hold great promise, translational research is still needed before they should enter mainstream clinical practice.

Human diseases account for complex traits that usually exhibit markedly diverse clinical manifestations coming from a series of pathogenic processes that shape heterogeneous phenotypes. Considering that correlation does not imply causation as well as population differences and/or inter-individual variability, disease-specific signatures are becoming critical for biomarker discovery. Untargeted metabolomics is deemed to be a powerful approach to delineate molecular pathways of prime interest. Metabotypes capture the interplay of genomics and environmental influences per se. Untargeted metabolomics share the charm of being not only hypothesis-driven but also hypothesis-generating. Notwithstanding, the applicability of untargeted metabolomics toward clinically relevant outcomes depend on wet- and dry-lab procedures in the context of elegant study designs with clear rationale. As ideal may be far from feasible, herein we provide recommendations to combat sample mishandling that adversely affect data outcomes and if so, deal with imbalanced datasets toward data integrity.

Recurrent cardiovascular events remain an enigma that accounts for30% of deaths worldwide. While heredity and human genetics variation play a key role, host-environment interactions offer a sound conceptual framework to dissect the molecular basis of recurrent cardiovascular events from genes and proteins to metabolites, thus accounting for environmental contributions as well. We report here a multiomics systems science approach so as to map interindividual variability in susceptibility to recurrent cardiovascular events. First, we performed data and text mining through a mixed-methods content analysis to select genomic variants, 10 single nucleotide polymorphisms, and microRNAs (miR-10a, miR-21, and miR-20a), minimizing bias in candidate marker selection. Next, we validated our

Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic, Mendelian disorders is amply demonstrated, clinical utility is less evident in polygenic traits, e.g., coronary artery disease or breast cancer. Polygenic risk scores (PRS) are subsets of individual genotypes designed to capture heritability of common traits, and hence to allow the stratification of risk of the trait in a population. We systematically reviewed the PubMed database for unequivocal evidence of clinical utility of polygenic risk scores, using stringent inclusion and exclusion criteria. While we identified studies demonstrating clinical validity in conditions where medical intervention based on a PRS is likely to benefit patient outcome, we did not identify a single study demonstrating unequivocally such a benefit, i.e. clinical utility. We conclude that while the routine use of PRSs hold great promise, translational research is still needed before they should enter mainstream clinical practice.

Simple Summary Cancer and inflammation share aberrant angiogenesis as a hallmark, and, thus, anti-angiogenetic strategies remain of key interest. Amifostine, which is already a drug on the market, may be of further benefit to patients also in the context of drug repurposing. To shed light on the anti-angiogenic properties of amifostine during human adult angiogenesis and grasp the early events of angiogenesis, we employed 3D cell untargeted metabolomics by liquid chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy in the presence of vascular endothelial growth factor-A or deferoxamine (pro-angiogenic factors that exhibit distinct angiogenesis induction profiles). Our findings reveal mechanism-specific inhibitory profiles of amifostine against VEGF-A- and deferoxamine-induced angiogenesis. Amifostine may serve as a dual radioprotective and anti-angiogenic agent in radiotherapy patients. Abstract Aberrant angiogenesis is a hallmark for cancer and inflammation, a key notion in drug repurposing efforts. To delineate the anti-angiogenic properties of amifostine in a human adult angiogenesis model via 3D cell metabolomics and upon a stimulant-specific manner, a 3D cellular angiogenesis assay that recapitulates cell physiology and drug action was coupled to untargeted metabolomics by liquid chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy. The early events of angiogenesis upon its most prominent stimulants (vascular endothelial growth factor-A or deferoxamine) were addressed by cell sprouting measurements. Data analyses consisted of a series of supervised and unsupervised methods as well as univariate and multivariate approaches to shed light on mechanism-specific inhibitory profiles. The 3D untargeted cell metabolomes were found to grasp the early events of angiogenesis. Evident of an initial and sharp response, the metabolites identified primarily span amino acids, sphingolipids, and nucleotides. Profiles were pathway or stimulant specific. The amifostine inhibition profile was rather similar to that of sunitinib, yet distinct, considering that the latter is a kinase inhibitor. Amifostine inhibited both. The 3D cell metabolomics shed light on the anti-angiogenic effects of amifostine against VEGF-A- and deferoxamine-induced angiogenesis. Amifostine may serve as a dual radioprotective and anti-angiogenic agent in radiotherapy patients.

In the “omics” era, incorporation of genomic medicine into clinical practice is greatly anticipated following recent scientific and technological advances. Currently a multidisciplinary agenda that involves government officials, funding agencies, industry leadership, healthcare providers, biomedicine researchers, and the general public is of outmost importance to “translate” human discoveries into human health. But although groundbreaking scientific findings are being revealed, the clinical application of genomic medicine and its acceptance in healthcare cannot be envisaged without sound science and evidence-based facts. A series of challenges exist from both scientific and policy perspectives at a global level. This chapter presents an overview of the current genomic medicine initiatives, both national and worldwide, which once successfully completed will help to expedite implementation of genomic medicine practices into the clinic.

Aim: Hemoglobinopathies exhibit a remarkable phenotypic diversity that restricts any safe association between molecular pathology and clinical outcomes. Patients & methods: Herein, we explored the role of genes involved in the nitric oxide biosynthesis and signaling pathway, implicated in the increase of fetal hemoglobin levels and response to hydroxyurea treatment, in 119 Hellenic patients with β-type hemoglobinopathies. Results: We show that two ASS1 genomic variants (namely, rs10901080 and rs10793902) can serve as pharmacogenomic biomarkers to predict hydroxyurea treatment efficacy in sickle cell disease/β-thalassemia compound heterozygous patients. Conclusion: These markers may exert their effect by inducing nitric oxide biosynthesis, either via altering splicing and/or miRNA binding, as predicted by in silico analysis, and ultimately, increase γ-globin levels, via guanylyl cyclase targeting.