Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Ligand Shaping in Induced Fit Docking of MraY Inhibitors. Polynomial Discriminant and Laplacian Operator as Biological Activity Descriptors

Docking—i.e., interaction of a small molecule (ligand) with a proteic structure (receptor)—represents the ground of drug action mechanism of the vast majority of bioactive chemicals. Ligand and receptor accommodate their geometry and energy, within this interaction, in the benefit of receptor–ligand complex. In an induced fit docking, the structure of ligand is most susceptible to changes in topology and energy, comparative to the receptor. These changes can be described by manifold hypersurfaces, in terms of polynomial discriminant and Laplacian operator. Such topological surfaces were represented for each MraY (phospho-MurNAc-pentapeptide translocase) inhibitor, studied before and after docking with MraY. Binding affinities of all ligands were calculated by this procedure. For each ligand, Laplacian and polynomial discriminant were correlated with the ligand minimum inhibitory concentration (MIC) retrieved from literature. It was observed that MIC is correlated with Laplacian and polynomial discriminant

Riemann-Symmetric-Space-Based Models in Screening for Gene Transfer Polymers

Today, gene transfer using polymers as transfer vectors is hardly studied. Some polymers have an excellent gene-carrying ability, but their cytotoxic and biocompatibility properties are not suitable for use. Thus, increased insight into the drug space of such structures is needed in the screening for suitable molecules. This study aimed to introduce a mathematical model of polymers suitable for genes transfer. In this regard, Riemann surfaces were used. The concerned polymers were taken from secondary published experimental data. The results show that symmetric Reimann spaces are suitable for further drug screening. The branch point values of Riemann surfaces are especially increased for the polymers suitable in gene transfer

Glomangioma Supply from Profunda Femoris Artery in Peripheral Artery Disease

This is a case report of a 5.6 cm glomangioma supplied by the femoral profunda artery in a 66-year-old male patient with severe peripheral artery disease. The patient complained of discomfort and mild pain at the place of the lesion and an accelerated growth rate in the last two months. A nodular mass located laterally on the left foot, elastic, covered with a thin skin, and mobile, was noted on the clinical exam. Doppler exam demonstrated an active vascular supply. CT angiography showed a femoral profunda artery blood supply and a severe asymptomatic bilateral peripheral artery disease (PAD). The lesion was removed entirely by surgery. A microscopy exam revealed a glomangioma. After surgery, the patient recovered unevenly. However, the patient experienced wound-healing issues that resolved after four weeks of surgery. Although the patient&rsquo;s PAD was severe, the lesion presented with a burst in dimensions weeks before surgery

Vaccine Coverage in Children Younger Than 1 Year of Age during Periods of High Epidemiological Risk: Are We Preparing for New Outbreaks?

Background: According to WHO, infectious disease control can be achieved if the vaccine coverage (VC) exceeds 90%. In recent years there has been a declining trend in VC which could lead to the recurrence of infectious diseases. Objectives: The study analyzed the determinants of VC and of parental decisions regarding immunization in children aged 0&ndash;1 year monitored during two high-risk epidemiological periods (the measles epidemic and the COVID-19 pandemic period). Methods: A retrospective observational cohort study-data regarding vaccination of children younger than 1 year of age during the periods January 2019&ndash;June 2019 (measles epidemic) and January 2020&ndash;June 2020 (COVID-19 pandemic) were analyzed. 2.850 children from 2019 and 2.823 children from 2020 were enrolled. Family physicians interacted with 2840 parents or legal guardians in 2019 and with 2800 parents or legal guardians in 2020, during the infants&rsquo; consults providing medical information and answer to their questions and worries regarding their immunization. Data on immunization schedules on the determinants of parents&rsquo; decisions regarding vaccination were evaluated. Results: During 2019&ndash;2020, VC has followed a declining trend for each type of vaccine included in the Romanian National Immunization Program; the most affected were infants aged 9&ndash;12 months during both periods: in 9-month aged infants, the MMR vaccine VC was 67.49% in 2019 vs. 59.04% in 2020 (p &lt; 0.004). In the 12 months aged infants, the MMR VC was 64.29% in 2019 vs. 55.88% in 2020 (p &lt; 0.005). For the Hexavalent vaccine administered at the age of 11 months, the VC was 71.59% in 2019 vs. 62.08% in 2020 (p &lt; 0.001). The determinants of parents&rsquo; decisions regarding vaccination included parental hesitance 2019&mdash;25% vs. 2020&mdash;35%, fear on side effects 2019&mdash;32% vs. 2020&mdash;45%, vaccination denial 2019&mdash;7% vs. 2020&mdash;10%. Conclusion: We found a declining trend in the VC in Romania during the epidemic and pandemic periods. The decrease in VC for MMR generated a major risk for new measles outbreaks Permanent awareness educational campaigns regarding infectious disease risk are needed, accompanied by the empowerment of primary care and the emergence of an immunization management program based on national regulatory legislation

Benzoquinoline Chemical Space: A Helpful Approach in Antibacterial and Anticancer Drug Design

Benzoquinolines are used in many drug design projects as starting molecules subject to derivatization. This computational study aims to characterize e benzoquinone drug space to ease future drug design processes based on these molecules. The drug space is composed of all benzoquinones, which are active on topoisomerase II and ATP synthase. Topological, chemical, and bioactivity spaces are explored using computational methodologies based on virtual screening and scaffold hopping and molecular docking, respectively. Topological space is a geometrical space in which the elements composing it can be defined as a set of neighbors (which satisfy a particular axiom). In such space, a chemical space can be defined as the property space spanned by all possible molecules and chemical compounds adhering to a given set of construction principles and boundary conditions. In this chemical space, the potentially pharmacologically active molecules form the bioactivity space. Results show a poly-morphological chemical space that suggests distinct characteristics. The chemical space is correlated with properties such as steric energy, the number of hydrogen bonds, the presence of halogen atoms, and membrane permeability-related properties. Lastly, novel chemical compounds (such as oxadiazole methybenzamide and floro methylcyclohexane diene) with drug-like potential, active on TOPO II and ATP synthase have been identified

Benzoquinoline Chemical Space: A Helpful Approach in Antibacterial and Anticancer Drug Design

Benzoquinolines are used in many drug design projects as starting molecules subject to derivatization. This computational study aims to characterize e benzoquinone drug space to ease future drug design processes based on these molecules. The drug space is composed of all benzoquinones, which are active on topoisomerase II and ATP synthase. Topological, chemical, and bioactivity spaces are explored using computational methodologies based on virtual screening and scaffold hopping and molecular docking, respectively. Topological space is a geometrical space in which the elements composing it can be defined as a set of neighbors (which satisfy a particular axiom). In such space, a chemical space can be defined as the property space spanned by all possible molecules and chemical compounds adhering to a given set of construction principles and boundary conditions. In this chemical space, the potentially pharmacologically active molecules form the bioactivity space. Results show a poly-morphological chemical space that suggests distinct characteristics. The chemical space is correlated with properties such as steric energy, the number of hydrogen bonds, the presence of halogen atoms, and membrane permeability-related properties. Lastly, novel chemical compounds (such as oxadiazole methybenzamide and floro methylcyclohexane diene) with drug-like potential, active on TOPO II and ATP synthase have been identified

Variations of VEGFR2 Chemical Space: Stimulator and Inhibitory Peptides

The kinase pathway plays a crucial role in blood vessel function. Particular attention is paid to VEGFR type 2 angiogenesis and vascular morphogenesis as the tyrosine kinase pathway is preferentially activated. In silico studies were performed on several peptides that affect VEGFR2 in both stimulating and inhibitory ways. This investigation aims to examine the molecular properties of VEGFR2, a molecule primarily involved in the processes of vasculogenesis and angiogenesis. These relationships were defined by the interactions between Vascular Endothelial Growth Factor receptor 2 (VEGFR2) and the structural features of the systems. The chemical space of the inhibitory peptides and stimulators was described using topological and energetic properties. Furthermore, chimeric models of stimulating and inhibitory proteins (for VEGFR2) were computed using the protein system structures. The interaction between the chimeric proteins and VEGFR was computed. The chemical space was further characterized using complex manifolds and high-dimensional data visualization. The results show that a slightly similar chemical area is shared by VEGFR2 and stimulating and inhibitory proteins. On the other hand, the stimulator peptides and the inhibitors have distinct chemical spaces

Linear and Branched PEIs (Polyethylenimines) and Their Property Space

A chemical property space defines the adaptability of a molecule to changing conditions and its interaction with other molecular systems determining a pharmacological response. Within a congeneric molecular series (compounds with the same derivatization algorithm and thus the same brute formula) the chemical properties vary in a monotonic manner, i.e., congeneric compounds share the same chemical property space. The chemical property space is a key component in molecular design, where some building blocks are functionalized, i.e., derivatized, and eventually self-assembled in more complex systems, such as enzyme-ligand systems, of which (physico-chemical) properties/bioactivity may be predicted by QSPR/QSAR (quantitative structure-property/activity relationship) studies. The system structure is determined by the binding type (temporal/permanent; electrostatic/covalent) and is reflected in its local electronic (and/or magnetic) properties. Such nano-systems play the role of molecular devices, important in nano-medicine. In the present article, the behavior of polyethylenimine (PEI) macromolecules (linear LPEI and branched BPEI, respectively) with respect to the glucose oxidase enzyme GOx is described in terms of their (interacting) energy, geometry and topology, in an attempt to find the best shape and size of PEIs to be useful for a chosen (nanochemistry) purpose

Protein Interaction with Dendrimer Monolayers: Energy and Surface Topology

Protein interaction with polymers layers is a keystone in designing bio-nano devices. Polyamidoamines (PAMAMs) are well-known polymers. Zero aromatic core dendrimers (ZAC) are molecules with no proven toxic effect in cultured cells. When coating nanodevices with enzymatic systems, active sites are disturbed by an interaction with the biosystem surface. Computational methods were used in order to simulate, characterize, and quantify protein&ndash;polymer interaction. Protein corona, i.e., surface proteins disposed on a viral membrane or nanodevice outer surface, are crucial in interactions with a potential pharmacological target or receptor. Corona symmetry has been observed in the Middle East respiratory syndrome-related coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As a protein alpha 1 antitrypsin&rsquo;s a crystallographic structure was chosen. Protein&ndash;mono dendrimer layer systems were generated using in silico methods in order to simulate their interaction. Interactions were quantified using topological and quantum mechanical strategies. Results showed that PAMAM and ZAC interact differently with alpha 1 antitrypsin. Energy and topological surfaces of protein vary accordingly with the dendrimer monolayer. Topological surfaces have a higher sensibility in describing the interactions