Personalized targeted therapy prescription in colorectal cancer using algorithmic analysis of RNA sequencing data.

BACKGROUND: Overall survival of advanced colorectal cancer (CRC) patients remains poor, and gene expression analysis could potentially complement detection of clinically relevant mutations to personalize CRC treatments. METHODS: We performed RNA sequencing of formalin-fixed, paraffin-embedded (FFPE) cancer tissue samples of 23 CRC patients and interpreted the data obtained using bioinformatic method Oncobox for expression-based rating of targeted therapeutics. Oncobox ranks cancer drugs according to the efficiency score calculated using target genes expression and molecular pathway activation data. The patients had primary and metastatic CRC with metastases in liver, peritoneum, brain, adrenal gland, lymph nodes and ovary. Two patients had mutations in NRAS, seven others had mutated KRAS gene. Patients were treated by aflibercept, bevacizumab, bortezomib, cabozantinib, cetuximab, crizotinib, denosumab, panitumumab and regorafenib as monotherapy or in combination with chemotherapy, and information on the success of totally 39 lines of therapy was collected. RESULTS: Oncobox drug efficiency score was effective biomarker that could predict treatment outcomes in the experimental cohort (AUC 0.77 for all lines of therapy and 0.91 for the first line after tumor sampling). Separately for bevacizumab, it was effective in the experimental cohort (AUC 0.87) and in 3 independent literature CRC datasets, n = 107 (AUC 0.84-0.94). It also predicted progression-free survival in univariate (Hazard ratio 0.14) and multivariate (Hazard ratio 0.066) analyses. Difference in AUC scores evidences importance of using recent biosamples for the prediction quality. CONCLUSION: Our results suggest that RNA sequencing analysis of tumor FFPE materials may be helpful for personalizing prescriptions of targeted therapeutics in CRC.

Gene Expression Signature of Endometrial Samples from Women with and without Endometriosis.

STUDY OBJECTIVE: To develop a prototype of a complex gene expression biomarker for the diagnosis of endometriosis on the basis of differences between the molecular signatures of the endometrium from women with and without endometriosis. DESIGN: Prospective observational cohort study. Evidence obtained from a well-designed, controlled trial without randomization. SETTING: Department of reproductive medicine and surgery, A.I. Evdokimov Moscow State University of Medicine and Dentistry. PATIENTS: A total of 33 women (aged 32-38 years) were included in this study. Patients with and without endometriosis were divided into 2 separate groups. The group composed of patients with endometriosis included 19 living patients with endometriosis who underwent laparoscopic excision of endometriosis. The control group included 6 living patients who underwent laparoscopic excision of incompetent uterine scar after cesarean section, with both surgically and histologically confirmed absence of endometriosis and adenomyosis. An additional control/verification group included various previously RNA-sequencing-profiled tissue samples (endocervix, ovarian surface epithelium) of 8 randomly selected healthy female cadaveric donors aged 32 to 38 years. The exclusion criteria for all patients were hormone therapy and any intrauterine device use for more than 1 year preceding surgery, as well as absence of other diseases of the uterus, fallopian tubes, and ovaries. INTERVENTIONS: Laparoscopic excision of endometriotic foci and hysteroscopy with endometrial sampling were performed. The cadaveric tissue samples included endocervix and ovarian surface epithelium. Endometrial sampling was obtained from the women in the control group. RNA sequencing was performed using Illumina HiSeq 3000 equipment (Illumina, Inc., San Diego, CA) for single-end sequencing. Unique bioinformatics algorithms were developed and validated using experimental and public gene expression datasets. MEASUREMENTS AND MAIN RESULTS: We generated a characteristic signature of 5 genes downregulated in the endometrium and endometriotic tissue of the patients with endometriosis, selected after comparison with the endometrium of the women without endometriosis. This gene signature showed a capacity for nearly perfect separation of all 52 analyzed tissue samples of the patients with endometriosis (endometrial as well as endometriotic samples) from the 14 tissue samples of both living and cadaveric donors without endometriosis (area under the curve = 0.982, Matthews correlation coefficient = 0.832). CONCLUSION: The gene signature of the endometrium identified in this study may potentially serve as a nonsurgical diagnostic method for endometriosis detection. Our data also suggest that the statistical method of 5-fold cross-validation of differential gene expression analysis can be used to generate robust gene signatures using real-world clinical data.

Analysis of miR-9-5p, miR-124-3p, miR-21-5p, miR-138-5p, and miR-1-3p in Glioblastoma Cell Lines and Extracellular Vesicles.

Glioblastoma (GBM), the most common primary brain tumor, is a complex and extremely aggressive disease. Despite recent advances in molecular biology, there is a lack of biomarkers, which would improve GBM's diagnosis, prognosis, and therapy. Here, we analyzed by qPCR the expression levels of a set of miRNAs in GBM and lower-grade glioma human tissue samples and performed a survival analysis in silico. We then determined the expression of same miRNAs and their selected target mRNAs in small extracellular vesicles (sEVs) of GBM cell lines. We showed that the expression of miR-21-5p was significantly increased in GBM tissue compared to lower-grade glioma and reference brain tissue, while miR-124-3p and miR-138-5p were overexpressed in reference brain tissue compared to GBM. We also demonstrated that miR-9-5p and miR-124-3p were overexpressed in the sEVs of GBM stem cell lines (NCH421k or NCH644, respectively) compared to the sEVs of all other GBM cell lines and astrocytes. VIM mRNA, a target of miR-124-3p and miR-138-5p, was overexpressed in the sEVs of U251 and U87 GBM cell lines compared to the sEVs of GBM stem cell line and also astrocytes. Our results suggest VIM mRNA, miR-9-5p miRNA, and miR-124-3p miRNA could serve as biomarkers of the sEVs of GBM cells.

Plasma exosomes stimulate breast cancer metastasis through surface interactions and activation of FAK signaling.

PURPOSE: The interaction between malignant cells and surrounding healthy tissues is a critical factor in the metastatic progression of breast cancer (BC). Extracellular vesicles, especially exosomes, are known to be involved in inter-cellular communication during cancer progression. In the study presented herein, we aimed to evaluate the role of circulating plasma exosomes in the metastatic dissemination of BC and to investigate the underlying molecular mechanisms of this phenomenon. METHODS: Exosomes isolated from plasma of healthy female donors were applied in various concentrations into the medium of MDA-MB-231 and MCF-7 cell lines. Motility and invasive properties of BC cells were examined by random migration and Transwell invasion assays, and the effect of plasma exosomes on the metastatic dissemination of BC cells was demonstrated in an in vivo zebrafish model. To reveal the molecular mechanism of interaction between plasma exosomes and BC cells, a comparison between un-treated and enzymatically modified exosomes was performed, followed by mass spectrometry, gene ontology, and pathway analysis. RESULTS: Plasma exosomes stimulated the adhesive properties, two-dimensional random migration, and transwell invasion of BC cells in vitro as well as their in vivo metastatic dissemination in a dose-dependent manner. This stimulatory effect was mediated by interactions of surface exosome proteins with BC cells and consequent activation of focal adhesion kinase (FAK) signaling in the tumor cells. CONCLUSIONS: Plasma exosomes have a potency to stimulate the metastasis-promoting properties of BC cells. This pro-metastatic property of normal plasma exosomes may have impact on the course of the disease and on its prognosis.

Cu nanoparticles constrain segmental dynamics of cross-linked polyethers: a trade-off between non-fouling and antibacterial properties.

Copper has a strong bactericidal effect against multi-drug resistant pathogens and polyethers are known for their resistance to biofilm formation. Herein, we combined Cu nanoparticles (NPs) and a polyether plasma polymer in the form of nanocomposite thin films and studied whether both effects can be coupled. Cu NPs were produced by magnetron sputtering via the aggregation in a cool buffer gas whereas polyether layers were synthesized by Plasma-Assisted Vapor Phase Deposition with poly(ethylene oxide) (PEO) used as a precursor. In situ specific heat spectroscopy and XPS analysis revealed the formation of a modified polymer layer around the NPs which propagates on the scale of a few nanometers from the Cu NP/polymer interface and then transforms into a bulk polymer phase. The chemical composition of the modified layer is found to be ether-deficient due to the catalytic influence of copper whereas the bulk polymer phase exhibits the chemical composition close to the original PEO. Two cooperative glass transition phenomena are revealed that belong to the modified polymer layer and the bulk phase. The former is characterized by constrained mobility of polymer segments which manifests itself via a 30 K increase of dynamic glass transition temperature. Furthermore, the modified layer is characterized by the heterogeneous structure which results in higher fragility of this layer as compared to the bulk phase. The Cu NPs/polyether thin films exhibit reduced protein adsorption; however, the constrained segmental dynamics leads to the deterioration of the non-fouling properties for ultra-thin polyether coatings. The films are found to have a bactericidal effect against multi-drug resistant Gram-positive Methicillin-Resistant Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa.

From Solid to Fluid: Novel Approaches in Neuromorphic Engineering.

Neuromorphic engineering is rapidly developing as an approach to mimicking processes in brains using artificial memristors, devices that change conductivity in response to the electrical field (resistive switching effect). Memristor-based neuromorphic systems can overcome the existing problems of slow and energy-inefficient computing that conventional processors face. In the Introduction, the basic principles of memristor operation and its applications are given. The history of switching in sandwich structures and granular metals is reviewed in the Historical Overview. Particular attention is paid to the fundamental articles from the pre-memristor era (the 1960s-70s), which demonstrated the first evidence of resistive switching and predicted the filamentary mechanism of switching. Multi-dimensionality in neuromorphic systems: Despite the powerful computational abilities of traditional memristor arrays, they cannot repeat many organizational characteristics of biological neural networks, i.e., their multi-dimensionality. This part reviews the unconventional nanowire- and nanoparticle-based neuromorphic systems that demonstrate incredible potential for use in reservoir computing due to the unique spiking change in conductance similar to firing in neurons. Liquid-based neuromorphic devices: The transition of neuromorphic systems from solid to liquid state broadens the possibilities for mimicking biological processes. In this section, ionic current memristors are reviewed and, the working principles of which bring us closer to the mechanisms of information transmittance in real synapses. Nanofluids: A novel direction in neuromorphic engineering linked to the application of nanofluids for the formation of reconfigurable nanoparticle networks with memristive properties is given in this section. The Conclusion t summarizes the bullet points of the Review and provides an outlook on the future of liquid-state neuromorphic systems.

One-step synthesis of photoluminescent nanofluids by direct loading of reactively sputtered cubic ZrN nanoparticles into organic liquids.

ZrN nanofluids may exhibit unique optoelectronic properties because of the matching of the solar spectrum with interband transitions and localized surface plasmon resonance (LSPR). Nevertheless, these nanofluids have scarcely been investigated, mainly because of the complexity of the current synthetic routes that involve aggressive chemicals and high temperatures. This work aims to validate reactive dc magnetron sputtering of zirconium in Ar/N2 as an environmentally benign, annealing-free method to produce 22 nm-sized, highly crystalline, stoichiometric, electrically conductive, and plasmonic ZrN nanoparticles (NPs) of cubic shape and to load them into vacuum-compatible liquids of different chemical compositions (polyethylene glycol (PEG), paraffin, and pentaphenyl trimethyl trisiloxane (PTT)) in one step. The nanofluids demonstrate LSPR in the red/near-IR range that gives them a bluish color in transmittance. The nanofluids also demonstrate complex photoluminescence behavior such that ZrN NPs enhance the photoluminescence (PL) intensity of paraffin and PEG, whereas the PL of PTT remains almost invariable. Based on DFT calculations, different energetic barriers to charge transfer between ZrN and the organic molecules are suggested as the main factors that influence the observed optoelectronic response. Overall, our study provides a novel approach to the synthesis of transition metal nitride nanofluids in an environmentally friendly manner, deepens the understanding of the interactions between ZrN and organic molecules, and unveils new optoelectronic phenomena in such systems.

Plasmonic Ag/Cu/PEG nanofluids prepared when solids meet liquids in the gas phase.

Since the time of Faraday's experiments, the optical response of plasmonic nanofluids has been tailored by the shape, size, concentration, and material of nanoparticles (NPs), or by mixing different types of NPs. To date, water-based liquids have been the most extensively investigated host media, while polymers, such as poly(ethylene glycol) (PEG), have frequently been added to introduce repulsive steric interactions and protect NPs from agglomeration. Here, we introduce an inverse system of non-aqueous nanofluids, in which Ag and Cu NPs are dispersed in PEG (400 g mol-1), with no solvents or chemicals involved. Our single-step approach comprises the synthesis of metal NPs in the gas phase using sputtering-based gas aggregation cluster sources, gas flow transport of NPs, and their deposition (optionally simultaneous) on the PEG surface. Using computational fluid dynamics simulations, we show that NPs diffuse into PEG at an average velocity of the diffusion front of the order of µm s-1, which is sufficient for efficient loading of the entire polymer bulk. We synthesize yellow Ag/PEG, green Cu/PEG, and blue Ag/Cu/PEG nanofluids, in which the color is given by the position of the plasmon resonance. NPs are prone to partial agglomeration and sedimentation, with a slower kinetics for Cu. Density functional theory calculations combined with UV-vis data and zeta-potential measurements prove that the surface oxidation to Cu2O and stronger electrostatic repulsion are responsible for the higher stability of Cu NPs. Adopting the De Gennes formalism, we estimate that PEG molecules adsorb on the NP surface in mushroom coordination, with the thickness of the adsorbed layer L < 1.4 nm, grafting density σ < 0.20, and the average distance between the grafted chains D > 0.8 nm. Such values provide sufficient steric barriers to retard, but not completely prevent, agglomeration. Overall, our approach offers an excellent platform for fundamental research on non-aqueous nanofluids, with metal-polymer and metal-metal interactions unperturbed by the presence of solvents or chemical residues.

Gene Expression-Based Signature Can Predict Sorafenib Response in Kidney Cancer.

Sorafenib is a tyrosine kinase inhibitory drug with multiple molecular specificities that is approved for clinical use in second-line treatments of metastatic and advanced renal cell carcinomas (RCCs). However, only 10-40% of RCC patients respond on sorafenib-containing therapies, and personalization of its prescription may help in finding an adequate balance of clinical efficiency, cost-effectiveness, and side effects. We investigated whether expression levels of known molecular targets of sorafenib in RCC can serve as prognostic biomarker of treatment response. We used Illumina microarrays to profile RNA expression in pre-treatment formalin-fixed paraffin-embedded (FFPE) samples of 22 metastatic or advanced RCC cases with known responses on next-line sorafenib monotherapy. Among them, nine patients showed partial response (PR), three patients-stable disease (SD), and 10 patients-progressive disease (PD) according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. We then classified PR + SD patients as "responders" and PD patients as "poor responders". We found that gene signature including eight sorafenib target genes was congruent with the drug response characteristics and enabled high-quality separation of the responders and poor responders [area under a receiver operating characteristic curve (AUC) 0.89]. We validated these findings on another set of 13 experimental annotated FFPE RCC samples (for 2 PR, 1 SD, and 10 PD patients) that were profiled by RNA sequencing and observed AUC 0.97 for 8-gene signature as the response classifier. We further validated these results in a series of qRT-PCR experiments on the third experimental set of 12 annotated RCC biosamples (for 4 PR, 3 SD, and 5 PD patients), where 8-gene signature showed AUC 0.83.

Experimental and Meta-Analytic Validation of RNA Sequencing Signatures for Predicting Status of Microsatellite Instability.

Microsatellite instability (MSI) is an important diagnostic and prognostic cancer biomarker. In colorectal, cervical, ovarian, and gastric cancers, it can guide the prescription of chemotherapy and immunotherapy. In laboratory diagnostics of susceptible tumors, MSI is routinely detected by the size of marker polymerase chain reaction products encompassing frequent microsatellite expansion regions. Alternatively, MSI status is screened indirectly by immunohistochemical interrogation of microsatellite binding proteins. RNA sequencing (RNAseq) profiling is an emerging source of data for a wide spectrum of cancer biomarkers. Recently, three RNAseq-based gene signatures were deduced for establishing MSI status in tumor samples. They had 25, 15, and 14 gene products with only one common gene. However, they were developed and tested on the incomplete literature of The Cancer Genome Atlas (TCGA) sampling and never validated experimentally on independent RNAseq samples. In this study, we, for the first time, systematically validated these three RNAseq MSI signatures on the literature colorectal cancer (CRC) (n = 619), endometrial carcinoma (n = 533), gastric cancer (n = 380), uterine carcinosarcoma (n = 55), and esophageal cancer (n = 83) samples and on the set of experimental CRC RNAseq samples (n = 23) for tumors with known MSI status. We found that all three signatures performed well with area under the curve (AUC) ranges of 0.94-1 for the experimental CRCs and 0.94-1 for the TCGA CRC, esophageal cancer, and uterine carcinosarcoma samples. However, for the TCGA endometrial carcinoma and gastric cancer samples, only two signatures were effective with AUC 0.91-0.97, whereas the third signature showed a significantly lower AUC of 0.69-0.88. Software for calculating these MSI signatures using RNAseq data is included.

Structure of Plasma (re)Polymerized Polylactic Acid Films Fabricated by Plasma-Assisted Vapour Thermal Deposition.

Plasma polymer films typically consist of very short fragments of the precursor molecules. That rather limits the applicability of most plasma polymerisation/plasma-enhanced chemical vapour deposition (PECVD) processes in cases where retention of longer molecular structures is desirable. Plasma-assisted vapour thermal deposition (PAVTD) circumvents this limitation by using a classical bulk polymer as a high molecular weight "precursor". As a model polymer in this study, polylactic acid (PLA) has been used. The resulting PLA-like films were characterised mostly by X-ray photoelectron spectroscopy (XPS) and nuclear magnetic resonance (NMR) spectroscopy. The molecular structure of the films was found to be tunable in a broad range: from the structures very similar to bulk PLA polymer to structures that are more typical for films prepared using PECVD. In all cases, PLA-like groups are at least partially preserved. A simplified model of the PAVTD process chemistry was proposed and found to describe well the observed composition of the films. The structure of the PLA-like films demonstrates the ability of plasma-assisted vapour thermal deposition to bridge the typical gap between the classical and plasma polymers.

DNA repair pathway activation features in follicular and papillary thyroid tumors, interrogated using 95 experimental RNA sequencing profiles.

DNA repair can prevent mutations and cancer development, but it can also restore damaged tumor cells after chemo and radiation therapy. We performed RNA sequencing on 95 human pathological thyroid biosamples including 17 follicular adenomas, 23 follicular cancers, 3 medullar cancers, 51 papillary cancers and 1 poorly differentiated cancer. The gene expression profiles are annotated here with the clinical and histological diagnoses and, for papillary cancers, with BRAF gene V600E mutation status. DNA repair molecular pathway analysis showed strongly upregulated pathway activation levels for most of the differential pathways in the papillary cancer and moderately upregulated pattern in the follicular cancer, when compared to the follicular adenomas. This was observed for the BRCA1, ATM, p53, excision repair, and mismatch repair pathways. This finding was validated using independent thyroid tumor expression dataset PRJEB11591. We also analyzed gene expression patterns linked with the radioiodine resistant thyroid tumors (n = 13) and identified 871 differential genes that according to Gene Ontology analysis formed two functional groups: (i) response to topologically incorrect protein and (ii) aldo-keto reductase (NADP) activity. We also found RNA sequencing reads for two hybrid transcripts: one in-frame fusion for well-known NCOA4-RET translocation, and another frameshift fusion of ALK oncogene with a new partner ARHGAP12. The latter could probably support increased expression of truncated ALK downstream from 4th exon out of 28. Both fusions were found in papillary thyroid cancers of follicular histologic subtype with node metastases, one of them (NCOA4-RET) for the radioactive iodine resistant tumor. The differences in DNA repair activation patterns may help to improve therapy of different thyroid cancer types under investigation and the data communicated may serve for finding additional markers of radioiodine resistance.

Dual-Mode Solution Plasma Processing for the Production of Chitosan/Ag Composites with the Antibacterial Effect.

The development of novel biocompatible and biodegradable materials for medical applications has been drawing significant interest in the scientific community for years. Particularly, chitosan loaded with silver nanoparticles (Ag NPs) has a strong antimicrobial potential and could be applied, for example, as wound dressing material. In this work, chitosan/Ag NP composites were produced utilizing a single-step plasma-solution process, which is simple and environmentally friendly. An acetic solution of chitosan containing AgNO3 was treated by the direct current (DC) atmospheric pressure glow discharge, with the liquid serving as either cathode or anode. The plasma-solution system with liquid anode is more useful for the production of Ag NPs. Nevertheless, the NP size is comparable for both cases. The plasma treatment with both polarities led to chitosan degradation. The cleavage of glucosidic chains mostly occurred in the system with the liquid cathode, whereas the side oxidation reactions took place when the solution served as the anode. The oxidation processes were possibly induced by the hydrogen peroxide H2O2 efficiently formed in the last case. The composite materials produced with both polarities of liquid electrode demonstrated the bactericidal action against Gram-negative Escherichia coli, Gram-positive Staphylococcus aureus, and Gram-positive Bacillus subtilis.

RNA Sequencing-Based Identification of Ganglioside GD2-Positive Cancer Phenotype.

The tumor-associated ganglioside GD2 represents an attractive target for cancer immunotherapy. GD2-positive tumors are more responsive to such targeted therapy, and new methods are needed for the screening of GD2 molecular tumor phenotypes. In this work, we built a gene expression-based binary classifier predicting the GD2-positive tumor phenotypes. To this end, we compared RNA sequencing data from human tumor biopsy material from experimental samples and public databases as well as from GD2-positive and GD2-negative cancer cell lines, for expression levels of genes encoding enzymes involved in ganglioside biosynthesis. We identified a 2-gene expression signature combining ganglioside synthase genes ST8SIA1 and B4GALNT1 that serves as a more efficient predictor of GD2-positive phenotype (Matthews Correlation Coefficient (MCC) 0.32, 0.88, and 0.98 in three independent comparisons) compared to the individual ganglioside biosynthesis genes (MCC 0.02-0.32, 0.1-0.75, and 0.04-1 for the same independent comparisons). No individual gene showed a higher MCC score than the expression signature MCC score in two or more comparisons. Our diagnostic approach can hopefully be applied for pan-cancer prediction of GD2 phenotypes using gene expression data.

Plasma Polymerization of Acrylic Acid for the Tunable Synthesis of Glassy and Carboxylated Nanoparticles.

Polymer nanoparticles (NPs) can be highly attractive in numerous applications, including biomedicine, where the use of inorganic matter may be detrimental for living tissues. In conventional wet chemistry, polymerization and functionalization of NPs with specific chemical groups involves complex and often numerous reactions. Here, we report on a solvent-free, single-step, low-temperature plasma-based synthesis of carboxylated NPs produced by the polymerization of acrylic acid under the conditions of a glow discharge. In a monomer-deficient regime, the strong fragmentation of monomer molecules by electron impact results in the formation of 15 nm-sized NPs with <1% retention of the carboxyl groups. In an energy-deficient regime, larger 90 nm-sized NPs are formed with better retention of carboxyl groups that reaches 16%. All types of NPs exhibit a glass transition above room temperature, which makes them highly stable in an aqueous environment with no dissolution or swelling. The NPs are also found to degrade thermally when heated above 150 °C, with a decrease in the mean NP size but with retention of the chemical composition. Thus, plasma polymerization proves to be a versatile approach for the production of polymer NPs with a tunable size distribution, chemical composition, and physical properties.

Retroelement-Linked Transcription Factor Binding Patterns Point to Quickly Developing Molecular Pathways in Human Evolution.

BACKGROUND: Retroelements (REs) are transposable elements occupying ~40% of the human genome that can regulate genes by providing transcription factor binding sites (TFBS). RE-linked TFBS profile can serve as a marker of gene transcriptional regulation evolution. This approach allows for interrogating the regulatory evolution of organisms with RE-rich genomes. We aimed to characterize the evolution of transcriptional regulation for human genes and molecular pathways using RE-linked TFBS accumulation as a metric. Methods: We characterized human genes and molecular pathways either enriched or deficient in RE-linked TFBS regulation. We used ENCODE database with mapped TFBS for 563 transcription factors in 13 human cell lines. For 24,389 genes and 3124 molecular pathways, we calculated the score of RE-linked TFBS regulation reflecting the regulatory evolution rate at the level of individual genes and molecular pathways. Results: The major groups enriched by RE regulation deal with gene regulation by microRNAs, olfaction, color vision, fertilization, cellular immune response, and amino acids and fatty acids metabolism and detoxication. The deficient groups were involved in translation, RNA transcription and processing, chromatin organization, and molecular signaling. Conclusion: We identified genes and molecular processes that have characteristics of especially high or low evolutionary rates at the level of RE-linked TFBS regulation in human lineage.

Correction: Nikitin, D., et al. Retroelement-Linked Transcription Factor Binding Patterns Point to Quickly Developing Molecular Pathways in Human Evolution. Cells 2019, 8, 130.

In the article 'Retroelement-Linked Transcription Factor Binding Patterns Point to Quickly Developing Molecular Pathways in Human Evolution,' a number of transcription factor binding sites (TFBS) mapped on all retroelement classes were incorrectly calculated as sum of TFBS numbers separately mapped on LINEs, SINEs and LTR retrotransposons/endogenous retroviruses (LR/ERVs) [...].

High FREM2 Gene and Protein Expression Are Associated with Favorable Prognosis of IDH-WT Glioblastomas.

World Health Organization grade IV diffuse gliomas, known as glioblastomas, are the most common malignant brain tumors, and they show poor prognosis. Multimodal treatment of surgery followed by radiation and chemotherapy is not sufficient to increase patient survival, which is 12 to 18 months after diagnosis. Despite extensive research, patient life expectancy has not significantly improved over the last decade. Previously, we identified FREM2 and SPRY1 as genes with differential expression in glioblastoma cell lines compared to nonmalignant astrocytes. In addition, the FREM2 and SPRY1 proteins show specific localization on the surface of glioblastoma cells. In this study, we explored the roles of the FREM2 and SPRY1 genes and their proteins in glioblastoma pathology using human tissue samples. We used proteomic, transcriptomic, and bioinformatics approaches to detect changes at different molecular levels. We demonstrate increased FREM2 protein expression levels in glioblastomas compared to reference samples. At the transcriptomic level, both FREM2 and SPRY1 show increased expression in tissue samples of different glioma grades compared to nonmalignant brain tissue. To broaden our experimental findings, we analyzed The Cancer Genome Atlas glioblastoma patient datasets. We discovered higher FREM2 and SPRY1 gene expression levels in glioblastomas compared to lower grade gliomas and reference samples. In addition, we observed that low FREM2 expression was associated with progression of IDH-mutant low-grade glioma patients. Multivariate analysis showed positive association between FREM2 and favorable prognosis of IDH-wild type glioblastoma. We conclude that FREM2 has an important role in malignant progression of glioblastoma, and we suggest deeper analysis to determine its involvement in glioblastoma pathology.

Retroelement-Linked H3K4me1 Histone Tags Uncover Regulatory Evolution Trends of Gene Enhancers and Feature Quickly Evolving Molecular Processes in Human Physiology.

BACKGROUND: Retroelements (REs) are mobile genetic elements comprising ~40% of human DNA. They can reshape expression patterns of nearby genes by providing various regulatory sequences. The proportion of regulatory sequences held by REs can serve a measure of regulatory evolution rate of the respective genes and molecular pathways. METHODS: We calculated RE-linked enrichment scores for individual genes and molecular pathways based on ENCODE project epigenome data for enhancer-specific histone modification H3K4me1 in five human cell lines. We identified consensus groups of molecular processes that are enriched and deficient in RE-linked H3K4me1 regulation. RESULTS: We calculated H3K4me1 RE-linked enrichment scores for 24,070 human genes and 3095 molecular pathways. We ranked genes and pathways and identified those statistically significantly enriched and deficient in H3K4me1 RE-linked regulation. CONCLUSION: Non-coding RNA genes were statistically significantly enriched by RE-linked H3K4me1 regulatory modules, thus suggesting their high regulatory evolution rate. The processes of gene silencing by small RNAs, DNA metabolism/chromatin structure, sensory perception/neurotransmission and lipids metabolism showed signs of the fastest regulatory evolution, while the slowest processes were connected with immunity, protein ubiquitination/degradation, cell adhesion, migration and interaction, metals metabolism/ion transport, cell death, intracellular signaling pathways.

Magnetron Sputtering of Polymeric Targets: From Thin Films to Heterogeneous Metal/Plasma Polymer Nanoparticles.

Magnetron sputtering is a well-known technique that is commonly used for the deposition of thin compact films. However, as was shown in the 1990s, when sputtering is performed at pressures high enough to trigger volume nucleation/condensation of the supersaturated vapor generated by the magnetron, various kinds of nanoparticles may also be produced. This finding gave rise to the rapid development of magnetron-based gas aggregation sources. Such systems were successfully used for the production of single material nanoparticles from metals, metal oxides, and plasma polymers. In addition, the growing interest in multi-component heterogeneous nanoparticles has led to the design of novel systems for the gas-phase synthesis of such nanomaterials, including metal/plasma polymer nanoparticles. In this featured article, we briefly summarized the principles of the basis of gas-phase nanoparticles production and highlighted recent progress made in the field of the fabrication of multi-component nanoparticles. We then introduced a gas aggregation source of plasma polymer nanoparticles that utilized radio frequency magnetron sputtering of a polymeric target with an emphasis on the key features of this kind of source. Finally, we presented and discussed three strategies suitable for the generation of metal/plasma polymer multi-core@shell or core-satellite nanoparticles: the use of composite targets, a multi-magnetron approach, and in-flight coating of plasma polymer nanoparticles by metal.