In this review, we focus on bioinformatic oncology as an integrative discipline that incorporates knowledge from the mathematical, physical, and computational fields to further the biomedical understanding of cancer. Before providing a deeper insight into the bioinformatics approach and utilities involved in oncology, we must understand what is a system biology framework and the genetic connection, because of the high heterogenicity of the backgrounds of people approaching precision medicine. In fact, it is essential to providing general theoretical information on genomics, epigenomics, and transcriptomics to understand the phases of multi-omics approach. We consider how to create a multi-omics model. In the last section, we describe the new frontiers and future perspectives of this field.
Alkaptonuria (AKU, OMIM: 203500) is an autosomal recessive disorder caused by mutations in the Homogentisate 1,2-dioxygenase (HGD) gene. A lack of standardized data, information and methodologies to assess disease severity and progression represents a common complication in ultra-rare disorders like AKU. This is the reason why we developed a comprehensive tool, called ApreciseKUre, able to collect AKU patients deriving data, to analyse the complex network among genotypic and phenotypic information and to get new insight in such multi-systemic disease. By taking advantage of the dataset, containing the highest number of AKU patient ever considered, it is possible to apply more sophisticated computational methods (such as machine learning) to achieve a first AKU patient stratification based on phenotypic and genotypic data in a typical precision medicine perspective. Thanks to our sufficiently populated and organized dataset, it is possible, for the first time, to extensively explore the phenotype–genotype relationships unknown so far. This proof of principle study for rare diseases confirms the importance of a dedicated database, allowing data management and analysis and can be used to tailor treatments for every patient in a more effective way.
Fast C-type inactivation confers distinctive functional properties to the hERG potassium channel, and its association to inherited and acquired cardiac arrythmias makes the study of the inactivation mechanism of hERG at the atomic detail of paramount importance. At present, two models have been proposed to describe C-type inactivation in K+-channels. Experimental data and computational work on the bacterial KcsA channel support the hypothesis that C-type inactivation results from a closure of the selectivity filter that sterically impedes ion conduction. Alternatively, recent experimental structures of a mutated Shaker channel revealed a widening of the extracellular portion of the selectivity filter, which might diminish conductance by interfering with the mechanism of ion permeation. Here, we performed molecular dynamics simulations of the wild-type hERG, a non-inactivating mutant (hERG-N629D), and a mutant that inactivates faster than the wild-type channel (hERG-F627Y) to find out which and if any of the two reported C-type inactivation mechanisms applies to hERG. Closure events of the selectivity filter were not observed in any of the simulated trajectories but instead, the extracellular section of the selectivity filter deviated from the canonical conductive structure of potassium channels. The degree of widening of the potassium binding sites at the extracellular entrance of the channel was directly related to the degree of inactivation with hERG-F627Y > wild-type hERG > hERG-N629D. These findings support the hypothesis that C-type inactivation in hERG entails a widening of the extracellular entrance of the channel rather than a closure of the selectivity filter.
Background - Worldwide, there are millions of chronic proton pump inhibitors (PPIs) users, often without a compelling indication. Evidence indicates that PPI treatment can increase mortality, in part due to a higher risk of QTc-related malignant arrhythmias. Drug-induced hypomagnesemia is currently believed to be the underlying mechanism, and therefore serum magnesium monitoring is recommended to minimize arrhythmic risk. However, recent data suggest that PPIs might also directly interfere with cardiac electrophysiology. To test this hypothesis, a translational study was performed using a combination of electrophysiology, molecular dynamics simulations, and population data. Methods - First, the effect of different PPIs on the ether-a-go-go -related-gene potassium channel (hERG) current was evaluated in HEK293-cells expressing hERG. Then, free energy calculations were performed to investigate the binding of these drugs to hERG. Finally, the impact of PPIs on the risk of QTc prolongation was assessed in a retrospective observational cohort of 3867 US Veterans, including 1289 PPI-treated subjects. Results - Clinically-relevant concentrations of different PPIs induced a significant inhibition of the hERG-current in-vitro , pantoprazole and lansoprazole being the most potent compounds. Atomic simulations demonstrated that such a blocking class-effect is likely due to direct PPIs binding to hERG-channel pore cavity. Accordingly, in a US Veterans cohort, PPI treatment was independently associated with a ~20-40% increased risk of QTc prolongation, also regardless of hypomagnesemia. Moreover, a synergistic interaction between PPIs and most of the traditional QT-prolonging risk factors was demonstrated. Conclusions - Altogether, this study provides, for the first time, strong evidence that PPIs can per se promote QTc prolongation, by directly inhibiting hERG function. A careful evaluation of the benefit/risk ratio is recommended whenever PPIs are administered in subjects with other QT-prolonging risk factors, even in the absence of hypomagnesemia.
X-ray structure of methyl-CpG binding domain (MBD) of MeCP2, an intrinsically disordered protein (IDP) involved in Rett syndrome, offers a rational basis for defining the spatial distribution for most of the sites where mutations responsible of Rett syndrome, RTT, occur. We have ascribed pathogenicity for mutations of amino acids bearing positively charged side chains, all located at the protein-DNA interface, as positive charge removal cause reduction of the MeCP2-DNA adduct lifetime. Pathogenicity of the frequent proline replacements, outside the DNA contact moiety of MBD, can be attributed to the role of this amino acid for maintaining both unfolded states for unbound MeCP2 and, at the same time, to favor some higher conformational order for stabilizing structural determinants required by protein activity. These hypotheses can be extended to transcription repressor domain, TRD, the other MeCP2-DNA interaction site and, in general, to all the IDP that interact with nucleic acids.
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