Publications by authors named "Alexander Gusev"

96 Publications

Graphene Nanoribbons: Prospects of Application in Biomedicine and Toxicity.

Nanomaterials (Basel) 2021 Sep 17;11(9). Epub 2021 Sep 17.

Research Institute for Environmental Science and Biotechnology, Derzhavin Tambov State University, 33 Internatsionalnaya St., 392000 Tambov, Russia.

Graphene nanoribbons are a type of graphene characterized by remarkable electrical and mechanical properties. This review considers the prospects for the application of graphene ribbons in biomedicine, taking into account safety aspects. According to the analysis of the recent studies, the topical areas of using graphene nanoribbons include mechanical, chemical, photo- and acoustic sensors, devices for the direct sequencing of biological macromolecules, including DNA, gene and drug delivery vehicles, and tissue engineering. There is evidence of good biocompatibility of graphene nanoribbons with human cell lines, but a number of researchers have revealed toxic effects, including cytotoxicity and genotoxicity. Moreover, the damaging effects of nanoribbons are often higher than those of chemical analogs, for instance, graphene oxide nanoplates. The possible mechanism of toxicity is the ability of graphene nanoribbons to damage the cell membrane mechanically, stimulate reactive oxidative stress (ROS) production, autophagy, and inhibition of proliferation, as well as apoptosis induction, DNA fragmentation, and the formation of chromosomal aberrations. At the same time, the biodegradability of graphene nanoribbons under the environmental factors has been proven. In general, this review allows us to conclude that graphene nanoribbons, as components of high-precision nanodevices and therapeutic agents, have significant potential for biomedical applications; however, additional studies of their safety are needed. Particular emphasis should be placed on the lack of information about the effect of graphene nanoribbons on the organism as a whole obtained from in vivo experiments, as well as about their ecological toxicity, accumulation, migration, and destruction within ecosystems.
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http://dx.doi.org/10.3390/nano11092425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469389PMC
September 2021

Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes with PD-1 Blockade in Non-Small Cell Lung Cancer.

Clin Cancer Res 2021 Sep 8;27(18):5131-5140. Epub 2021 Jul 8.

Department of Medicine, University of California San Francisco, San Francisco, California.

Purpose: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE).

Experimental Design: In patients with non-small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI.

Results: Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52-0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29-1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08-1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit.

Conclusions: Thyroid irAEs were associated with response to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0921DOI Listing
September 2021

Gene Fusions Create Partner and Collateral Dependencies Essential to Cancer Cell Survival.

Cancer Res 2021 Aug 7;81(15):3971-3984. Epub 2021 Jun 7.

Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

Gene fusions frequently result from rearrangements in cancer genomes. In many instances, gene fusions play an important role in oncogenesis; in other instances, they are thought to be passenger events. Although regulatory element rearrangements and copy number alterations resulting from these structural variants are known to lead to transcriptional dysregulation across cancers, the extent to which these events result in functional dependencies with an impact on cancer cell survival is variable. Here we used CRISPR-Cas9 dependency screens to evaluate the fitness impact of 3,277 fusions across 645 cell lines from the Cancer Dependency Map. We found that 35% of cell lines harbored either a fusion partner dependency or a collateral dependency on a gene within the same topologically associating domain as a fusion partner. Fusion-associated dependencies revealed numerous novel oncogenic drivers and clinically translatable alterations. Broadly, fusions can result in partner and collateral dependencies that have biological and clinical relevance across cancer types. SIGNIFICANCE: This study provides insights into how fusions contribute to fitness in different cancer contexts beyond partner-gene activation events, identifying partner and collateral dependencies that may have direct implications for clinical care.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338889PMC
August 2021

Clinical Inflection Point Detection on the Basis of EHR Data to Identify Clinical Trial-Ready Patients With Cancer.

JCO Clin Cancer Inform 2021 06;5:622-630

Division of Population Sciences, the Knowledge Systems Group, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Purpose: To inform precision oncology, methods are needed to use electronic health records (EHRs) to identify patients with cancer who are experiencing clinical inflection points, consistent with worsening prognosis or a high propensity to change treatment, at specific time points. Such patients might benefit from real-time screening for clinical trials.

Methods: Using serial unstructured imaging reports for patients with solid tumors or lymphoma participating in a single-institution precision medicine study, we trained a deep neural network natural language processing (NLP) model to dynamically predict patients' prognoses and propensity to start new palliative-intent systemic therapy within 30 days. Model performance was evaluated using Harrell's c-index (for prognosis) and the area under the receiver operating characteristic curve (AUC; for new treatment and new clinical trial enrollment). Associations between model outputs and manual annotations of cancer progression were also evaluated using the AUC.

Results: A deep NLP model was trained and evaluated using 302,688 imaging reports for 16,780 patients. In a held-out test set of 34,770 reports for 1,952 additional patients, the model predicted survival with a c-index of 0.76 and initiation of new treatment with an AUC of 0.77. Model-generated prognostic scores were associated with annotation of cancer progression on the basis of manual EHR review (n = 1,488 reports for 110 patients with lung or colorectal cancer) with an AUC of 0.78, and predictions of new treatment were associated with annotation of cancer progression on the basis of manual EHR review with an AUC of 0.84.

Conclusion: Training a deep NLP model to identify clinical inflection points among patients with cancer is feasible. This approach could identify patients who may benefit from real-time targeted clinical trial screening interventions at health system scale.
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http://dx.doi.org/10.1200/CCI.20.00184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240790PMC
June 2021

Alterations and Response to Immunotherapy in Solid Tumors.

Clin Cancer Res 2021 Jul 1;27(14):4025-4035. Epub 2021 Jun 1.

Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Purpose: Immune checkpoint inhibitors (ICI) have shown clinical benefit in many types of metastatic cancers with only a few predictive biomarkers identified so far. is commonly altered in human cancers, but prior studies have provided conflicting evidence regarding the association between genomic alterations (GA) and response to ICIs. Herein, we examined the impact of loss-of-function alterations on response and survival in patients treated with ICIs.

Experimental Design: We studied the association between loss-of-function alterations and the response to ICIs in two independent cohorts of six different cancer types. Seven hundred and eighty-nine patients treated at Dana-Farber Cancer Institute (DFCI; Boston, MA) and 1,250 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY) were included in the final analysis. Patients' tumors were sequenced using Oncopanel or MSK-IMPACT. RNA sequencing data from The Cancer Genome Atlas and IMvigor210 were used to investigate differences in the tumor microenvironment.

Results: In the DFCI cohort, GAs were associated with poor response and survival in patients with urothelial carcinoma treated with ICIs, but not those treated with platinum-based therapy. Similarly, GAs were associated with worse outcomes in the MSKCC urothelial carcinoma cohort treated with ICIs. There was no association of status with ICI treatment outcome in five other cancers: esophagogastric, head and neck, non-small cell lung, renal cell carcinoma, and melanoma. Immuno-inflammatory pathways were significantly reduced in expression in altered tumors.

Conclusions: Our data show that GAs were associated with reduced benefit from ICI therapy in urothelial carcinoma as well as changes in the tumor-immune microenvironment.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0575DOI Listing
July 2021

Hyperfine Interactions in the NV-C Quantum Registers in Diamond Grown from the Azaadamantane Seed.

Nanomaterials (Basel) 2021 May 14;11(5). Epub 2021 May 14.

Institute for Quantum Optics, Ulm University, 89069 Ulm, Germany.

Nanostructured diamonds hosting optically active paramagnetic color centers (NV, SiV, GeV, etc.) and hyperfine-coupled with them quantum memory C nuclear spins situated in diamond lattice are currently of great interest to implement emerging quantum technologies (quantum information processing, quantum sensing and metrology). Current methods of creation such as electronic-nuclear spin systems are inherently probabilistic with respect to mutual location of color center electronic spin and C nuclear spins. A new bottom-up approach to fabricate such systems is to synthesize first chemically appropriate diamond-like organic molecules containing desired isotopic constituents in definite positions and then use them as a seed for diamond growth to produce macroscopic diamonds, subsequently creating vacancy-related color centers in them. In particular, diamonds incorporating coupled NV-C spin systems (quantum registers) with specific mutual arrangements of NV and C can be obtained from anisotopic azaadamantane molecule. Here we predict the characteristics of hyperfine interactions () for the NV-C systems in diamonds grown from various isotopically substituted azaadamantane molecules differing in C position in the seed, as well as the orientation of the NV center in the post-obtained diamond. We used the spatial and data simulated earlier for the H-terminated cluster C[NV]H. The data obtained can be used to identify (and correlate with the seed used) the specific NV-C spin system by measuring, e.g., the -induced splitting of the m = ±1 sublevels of the NV center in optically detected magnetic resonance (ODMR) spectra being characteristic for various NV-C systems.
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http://dx.doi.org/10.3390/nano11051303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156205PMC
May 2021

Leveraging expression from multiple tissues using sparse canonical correlation analysis and aggregate tests improves the power of transcriptome-wide association studies.

PLoS Genet 2021 04 8;17(4):e1008973. Epub 2021 Apr 8.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.

Transcriptome-wide association studies (TWAS) test the association between traits and genetically predicted gene expression levels. The power of a TWAS depends in part on the strength of the correlation between a genetic predictor of gene expression and the causally relevant gene expression values. Consequently, TWAS power can be low when expression quantitative trait locus (eQTL) data used to train the genetic predictors have small sample sizes, or when data from causally relevant tissues are not available. Here, we propose to address these issues by integrating multiple tissues in the TWAS using sparse canonical correlation analysis (sCCA). We show that sCCA-TWAS combined with single-tissue TWAS using an aggregate Cauchy association test (ACAT) outperforms traditional single-tissue TWAS. In empirically motivated simulations, the sCCA+ACAT approach yielded the highest power to detect a gene associated with phenotype, even when expression in the causal tissue was not directly measured, while controlling the Type I error when there is no association between gene expression and phenotype. For example, when gene expression explains 2% of the variability in outcome, and the GWAS sample size is 20,000, the average power difference between the ACAT combined test of sCCA features and single-tissue, versus single-tissue combined with Generalized Berk-Jones (GBJ) method, single-tissue combined with S-MultiXcan, UTMOST, or summarizing cross-tissue expression patterns using Principal Component Analysis (PCA) approaches was 5%, 8%, 5% and 38%, respectively. The gain in power is likely due to sCCA cross-tissue features being more likely to be detectably heritable. When applied to publicly available summary statistics from 10 complex traits, the sCCA+ACAT test was able to increase the number of testable genes and identify on average an additional 400 additional gene-trait associations that single-trait TWAS missed. Our results suggest that aggregating eQTL data across multiple tissues using sCCA can improve the sensitivity of TWAS while controlling for the false positive rate.
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http://dx.doi.org/10.1371/journal.pgen.1008973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057593PMC
April 2021

An Evolution Based on Various Energy Strategies.

Entropy (Basel) 2021 Mar 8;23(3). Epub 2021 Mar 8.

Technical Physics Department, Ural Federal University, 19 Mira St., 620002 Ekaterinburg, Russia.

The simplest model of the evolution of agents with different energy strategies is considered. The model is based on the most general thermodynamic ideas and includes the procedures for selection, inheritance, and variability. The problem of finding a universal strategy (principle) as a selection of possible competing strategies is solved. It is shown that when there is non-equilibrium between the medium and agents, a direction in the evolution of agents arises, but at the same time, depending on the conditions of the evolution, different strategies can be successful. However, for this case, the simulation results reveal that in the presence of significant competition of agents, the strategy that has the maximum total energy dissipation of agents arising as a result of evolution turns out to be successful. Thus, it is not the specific strategy that is universal, but the maximization of dissipation. This result discovers an interesting connection between the basic principles of Darwin-Wallace evolution and the maximum entropy production principle.
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http://dx.doi.org/10.3390/e23030317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998875PMC
March 2021

Prediction of severe immune-related adverse events requiring hospital admission in patients on immune checkpoint inhibitors: study of a population level insurance claims database from the USA.

J Immunother Cancer 2021 03;9(3)

Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA

Background: Immune-related adverse events (irAEs) are a serious side effect of immune checkpoint inhibitor (ICI) therapy for patients with advanced cancer. Currently, predisposing risk factors are undefined but understanding which patients are at increased risk for irAEs severe enough to require hospitalization would be beneficial to tailor treatment selection and monitoring.

Methods: We performed a retrospective review of patients with cancer treated with ICIs using unidentifiable claims data from an Aetna nationwide US health insurance database from January 3, 2011 to December 31, 2019, including patients with an identified primary cancer and at least one administration of an ICI. Regression analyses were performed. Main outcomes were incidence of and factors associated with irAE requiring hospitalization in ICI therapy.

Results: There were 68.8 million patients identified in the national database, and 14 378 patients with cancer identified with at least 1 administration of ICI in the study period. Patients were followed over 19 117 patient years and 504 (3.5%) developed an irAE requiring hospitalization. The incidence of irAEs requiring hospitalization per patient ICI treatment year was 2.6%, rising from 0% (0/71) in 2011 to 3.7% (93/2486) in 2016. Combination immunotherapy (OR: 2.44, p<0.001) was associated with increased odds of developing irAEs requiring hospitalization, whereas older patients (OR 0.98 per additional year, p<0.001) and those with non-lung cancer were associated with decreased odds of irAEs requiring hospitalization (melanoma OR: 0.70, p=0.01, renal cell carcinoma OR: 0.71, p=0.03, other cancers OR: 0.50, p<0.001). Sex, region, zip-code-imputed income, and zip-code unemployment were not associated with incidence of irAE requiring hospitalization. Prednisone (72%) and methylprednisolone (25%) were the most common immunosuppressive treatments identified in irAE hospitalizations.

Conclusions: We found that 3.5% of patients initiating ICI therapy experienced irAEs requiring hospitalization and immunosuppression. The odds of irAEs requiring hospitalization were higher with younger age, treatment with combination ICI therapy (cytotoxic T lymphocyte-associated 4 and programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1)), and lower for other cancers compared with patients on PD-1 or PD-L1 inhibitors with lung cancer. This evidence from the first nationwide study of irAEs requiring hospitalization in the USA identified the real-world epidemiology, risk factors, and treatment patterns of these irAEs which may guide treatment and management decisions.
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http://dx.doi.org/10.1136/jitc-2020-001935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016099PMC
March 2021

Trans-ethnic variation in germline variants of patients with renal cell carcinoma.

Cell Rep 2021 03;34(13):108926

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine and Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Prior studies of the renal cell carcinoma (RCC) germline landscape investigated predominantly patients of European ancestry. We examine the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 1,829 patients with RCC from various ancestries. Overall, P/LP variants are found in 17% of patients, among whom 10.3% harbor one or more clinically actionable variants with potential preventive or therapeutic utility. Patients of African ancestry with RCC harbor significantly more P/LP variants in FH compared to patients of non-African ancestry with RCC and African controls from the Genome Aggregation Database (gnomAD). Patients of non-African ancestry have significantly more P/LP variants in CHEK2 compared to patients of African ancestry with RCC and non-Finnish Europeans controls. Non-Africans with RCC have more actionable variants compared to Africans with RCC. This work helps understand the underlying biological differences in RCC between Africans and non-Africans and paves the way to more comprehensive genomic characterization of underrepresented populations.
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http://dx.doi.org/10.1016/j.celrep.2021.108926DOI Listing
March 2021

Side effects of traditional pesticides on soil microbial respiration in orchards on the Russian Black Sea coast.

Chemosphere 2021 Jul 20;275:130040. Epub 2021 Feb 20.

Instituto de Ingeniería Agraria y Suelos, Facultad de Ciencias Agrarias y Alimentarias, Universidad Austral de Chile, Valdivia, Chile. Electronic address:

Agricultural use of pesticides has greatly increased worldwide over the last several decades, affecting soil microorganisms. Microbial basal respiration and substrate-induced respiration rates are commonly used to assess the detrimental effects of pesticides on soil quality. The goal of the present study was (1) to compare the impact of different pesticides on soil microbial respiration under field conditions, and (2) to characterize the recovery time of soil microbial respiration after pesticide application. The following pesticides were used in the present study: chlorpyrifos, phosalone, dimethoate (organophosphorus insecticides), λ-cyhalothrin (pyrethroid insecticide), and kresoxim-methyl (fungicide). The application of all the pesticides at commercial doses led to a decrease in soil microbial respiration. The inhibition of basal respiration and substrate-induced respiration rate decreased in the following order: chlorpyrifos > phosalone > dimethoate > λ-cyhalothrin ≈ kresoxim-methyl. Among all the pesticides assessed, chlorpyrifos showed the highest toxicity as well as the highest persistence. Several of the observed results differed greatly from previous studies; thus, local assessments are highly advisable. Given that environmental concerns can be a key decision factor for pesticide selection, assessment of different pesticides-such as undertaken in this study-could help farmers to choose the most appropriate pesticide.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130040DOI Listing
July 2021

In Vivo Study of Entero- and Hepatotoxicity of Silver Nanoparticles Stabilized with Benzyldimethyl-[3-myristoylamine)-propyl]ammonium Chloride (Miramistin) to CBF1 Mice upon Enteral Administration.

Nanomaterials (Basel) 2021 Jan 27;11(2). Epub 2021 Jan 27.

Department of Chemistry, Lomonosov Moscow State University, 1-3 Lenin Hills, 119991 Moscow, Russia.

Silver nanoparticles (AgNPs) are the most widely studied antimicrobial nanomaterials. However, their use in biomedicine is currently limited due to the availability of data that prove the nanosilver toxicity associated primarily with oxidative stress development in mammalian cells. The surface modification of AgNPs is a potent technique of improvement of their biocompatibility. The synthetic or natural compounds that combine zero or low toxicity towards human and animal organisms with inherent antimicrobial properties are the most promising stabilizing agents, their use would also minimize the risks of microorganisms developing resistance to silver-based materials. We used a simple technique to obtain 30-60 nm AgNPs stabilized with benzyldimethyl[3-myristoylamine)-propyl]ammonium chloride monohydrate (BAC)-a well-known active ingredient of many antibacterial drugs. The objective of the study was to assess the AgNPs-BAC entero- and hepatotoxicity to CBF1 mice upon enteral administration. The animals were exposed to 0.8-7.5 mg/kg doses of AgNPs-BAC in the acute and to 0.05-2.25 mg/kg doses of AgNPs-BAC in the subacute experiments. No significant entero- and hepatotoxic effects following a single exposure to doses smaller than 4 mg/kg were detected. Repeated exposure to the doses of AgNPs-BAC below 0.45 mg/kg and to the doses of BAC below 0.5 mg/kg upon enteral administration also led to no adverse effects. During the acute experiment, the higher AgNPs-BAC dose resulted in increased quantities of aminotransferases and urea, as well as the albumin-globulin ratio shift, which are indicative of inflammatory processes. Besides, the relative mass of the liver of mice was smaller compared to the control. During the subacute experiment, the groups treated with the 0.25-2.25 mg/kg dose of AgNPs-BAC had a lower weight gain rate compared to the control, while the groups treated with the 2.25 mg/kg dose of AgNPs-BAC showed statistically significant variations in the blood serum transaminases activity, which indicated hepatosis. It should be noted that the spleen and liver of the animals from the groups treated with the 0.45 and 2.25 mg/kg dose of AgNPs-BAC were more than two times smaller compared to the control. In the intestines of some animals from the group treated with the 2.25 mg/kg dose of AgNPs-BAC small areas of hyperemia and enlarged Peyer's patches were observed. Histological examination confirmed the initial stages of the liver and intestinal wall inflammation.
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http://dx.doi.org/10.3390/nano11020332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911341PMC
January 2021

Genetic Ancestry Contributes to Somatic Mutations in Lung Cancers from Admixed Latin American Populations.

Cancer Discov 2021 03 2;11(3):591-598. Epub 2020 Dec 2.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Inherited lung cancer risk, particularly in nonsmokers, is poorly understood. Genomic and ancestry analysis of 1,153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden, and specific driver mutations in , and . A local Native American ancestry risk score was more strongly correlated with mutation frequency compared with global ancestry correlation, suggesting that germline genetics (rather than environmental exposure) underlie these disparities. SIGNIFICANCE: The frequency of somatic and mutations in lung cancer varies by ethnicity, but we do not understand why. Our study suggests that the variation in and mutation frequency is associated with genetic ancestry and suggests further studies to identify germline alleles that underpin this association...
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http://dx.doi.org/10.1158/2159-8290.CD-20-1165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933062PMC
March 2021

Identity-by-descent detection across 487,409 British samples reveals fine scale population structure and ultra-rare variant associations.

Nat Commun 2020 11 30;11(1):6130. Epub 2020 Nov 30.

Department of Statistics, University of Oxford, Oxford, UK.

Detection of Identical-By-Descent (IBD) segments provides a fundamental measure of genetic relatedness and plays a key role in a wide range of analyses. We develop FastSMC, an IBD detection algorithm that combines a fast heuristic search with accurate coalescent-based likelihood calculations. FastSMC enables biobank-scale detection and dating of IBD segments within several thousands of years in the past. We apply FastSMC to 487,409 UK Biobank samples and detect ~214 billion IBD segments transmitted by shared ancestors within the past 1500 years, obtaining a fine-grained picture of genetic relatedness in the UK. Sharing of common ancestors strongly correlates with geographic distance, enabling the use of genomic data to localize a sample's birth coordinates with a median error of 45 km. We seek evidence of recent positive selection by identifying loci with unusually strong shared ancestry and detect 12 genome-wide significant signals. We devise an IBD-based test for association between phenotype and ultra-rare loss-of-function variation, identifying 29 association signals in 7 blood-related traits.
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http://dx.doi.org/10.1038/s41467-020-19588-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704644PMC
November 2020

Toxicity of Carbon, Silicon, and Metal-Based Nanoparticles to Sea Urchin Strongylocentrotus Intermedius.

Nanomaterials (Basel) 2020 Sep 13;10(9). Epub 2020 Sep 13.

Far Eastern Federal University, Sukhanova 8, 690950 Vladivostok, Russia.

With the increasing annual production of nanoparticles (NPs), the risks of their harmful influence on the environment and human health are rising. However, our knowledge about the mechanisms of interaction between NPs and living organisms is limited. Prior studies have shown that echinoderms, and especially sea urchins, represent one of the most suitable models for risk assessment in environmental nanotoxicology. To the best of the authors' knowledge, the sea urchin has not been used for testing the toxicity of NPs. The present study was designed to determine the effect of 10 types of common NPs on spermatozoa activity, egg fertilization, and early stage of embryo development of the sea urchin . In this research, we used two types of multiwalled carbon nanotubes (CNT-1 and CNT-2), two types of carbon nanofibers (CNF-1 and CNF-2), two types of silicon nanotubes (SNT-1 and SNT-2), nanocrystals of cadmium and zinc sulfides (CdS and ZnS), gold NPs (Au), and titanium dioxide NPs (TiO). The results of the embryotoxicity test showed the following trend in the toxicity level of used NPs: Au > SNT-2 > SNT-1 > CdS > ZnS > CNF-2 > CNF-1 > TiO > CNT-1 > CNT-2. This research confirmed that the sea urchin can be considered as a sensitive and stable test model in marine nanotoxicology.
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http://dx.doi.org/10.3390/nano10091825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557930PMC
September 2020

New Relevant Descriptor of Linear QNAR Models for Toxicity Assessment of Silver Nanoparticles.

Nanomaterials (Basel) 2020 Jul 25;10(8). Epub 2020 Jul 25.

Department of Chemistry, Lomonosov Moscow State University, Lenin Hills 1-3, 119991 Moscow, Russia.

The use of silver nanoparticles (NPs) in medical, industrial and agricultural fields is becoming more widespread every year. This leads to an increasing number of experimental toxicological and microbiological studies of silver NPs aimed at establishing the risk-benefit ratio for their application. The following key parameters affecting the biological activity of silver dispersions are traditionally taken into consideration: mean diameter of NPs, surface potential of NPs and equilibrium concentration of Ag. These characteristics are mainly predetermined by the chemical nature of the capping agent used for stabilization. However, the extent to which they influence the biological activity and the toxicity of silver NPs varies greatly. In this work, dispersions of silver NPs stabilized with a wide array of substances of different chemical nature were used for quantitative evaluation of whether the various measurable properties of silver NPs fit as descriptors of linear QNAR (quantitative nanostructure-activity relationship) models for silver NP toxicity evaluation with respect to a model eukaryotic microorganism- yeast cells. It was shown that among the factors that determine silver NP toxicity, the charge of particles, their colloidal stability and the ability to generate Ag ions carry more importance than the descriptors related to the particle size. A significant synergistic effect between the ζ-potential and the colloidal stability of silver NPs on their toxicity was also discovered. Following this, a new descriptor has been proposed for the integral characterization of the silver dispersion colloidal stability. According to the obtained data, it can be considered applicable for building QNAR models of higher efficacy. The validity testing of the proposed model for theoretical prediction of silver NP toxicity using a wide range of living organisms has shown that this new descriptor correlates with toxicity much better compared to most traditionally used descriptors. Consequently, it seems promising in terms of being used not only in situations involving the rather narrow array of the objects tested, but also for the construction of silver NP toxicity models with respect to other living organisms.
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http://dx.doi.org/10.3390/nano10081459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466614PMC
July 2020

Nanotoxicity of ZrS Probed in a Bioluminescence Test on Bacteria: The Effect of Evolving HS.

Nanomaterials (Basel) 2020 Jul 18;10(7). Epub 2020 Jul 18.

Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.

Materials from a large family of transition metal trichalcogenides (TMTCs) attract considerable attention because of their potential applications in electronics, optoelectronics and energy storage, but information on their toxicity is lacking. In this study, we investigated the toxicity of ZrS, a prominent TMTC material, toward photoluminescent bacteria in a bioluminescence test. We found that freshly prepared ZrS suspensions in physiological saline solution with concentrations as high as 1 g/L did not exhibit any toxic effects on the bacteria. However, ZrS suspensions that were stored for 24 h prior to the bioluminescence tests were very toxic to the bacteria and inhibited their emission, even at concentrations down to 0.001 g/L. We explain these observations by the aqueous hydrolysis of ZrS, which resulted in the formation of ZrO on the surface of ZrS particles and the release of toxic HS. The formation of ZrO was confirmed by the XPS analysis, while the characteristic HS smell was noticeable for the 24 h suspensions. This study demonstrates that while ZrS appears to be intrinsically nontoxic to photoluminescent bacteria, it may exhibit high toxicity in aqueous media. The results of this study can likely be extended to other transition metal chalcogenides, as their toxicity in aqueous solutions may also increase over time due to hydrolysis and the formation of HS. The results of this study also demonstrate that since many systems involving nanomaterials are unstable and evolve over time in various ways, their toxicity may evolve as well, which should be considered for relevant toxicity tests.
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http://dx.doi.org/10.3390/nano10071401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407145PMC
July 2020

Optimized homomorphic encryption solution for secure genome-wide association studies.

BMC Med Genomics 2020 07 21;13(Suppl 7):83. Epub 2020 Jul 21.

Duality Technologies, Inc., Newark, NJ, USA.

Background: Genome-Wide Association Studies (GWAS) refer to observational studies of a genome-wide set of genetic variants across many individuals to see if any genetic variants are associated with a certain trait. A typical GWAS analysis of a disease phenotype involves iterative logistic regression of a case/control phenotype on a single-neuclotide polymorphism (SNP) with quantitative covariates. GWAS have been a highly successful approach for identifying genetic-variant associations with many poorly-understood diseases. However, a major limitation of GWAS is the dependence on individual-level genotype/phenotype data and the corresponding privacy concerns.

Methods: We present a solution for secure GWAS using homomorphic encryption (HE) that keeps all individual data encrypted throughout the association study. Our solution is based on an optimized semi-parallel GWAS compute model, a new Residue-Number-System (RNS) variant of the Cheon-Kim-Kim-Song (CKKS) HE scheme, novel techniques to switch between data encodings, and more than a dozen crypto-engineering optimizations.

Results: Our prototype can perform the full GWAS computation for 1,000 individuals, 131,071 SNPs, and 3 covariates in about 10 minutes on a modern server computing node (with 28 cores). Our solution for a smaller dataset was awarded co-first place in iDASH'18 Track 2: "Secure Parallel Genome Wide Association Studies using HE".

Conclusions: Many of the HE optimizations presented in our paper are general-purpose, and can be used in solving challenging problems with large datasets in other application domains.
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http://dx.doi.org/10.1186/s12920-020-0719-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372898PMC
July 2020

Prostate cancer reactivates developmental epigenomic programs during metastatic progression.

Nat Genet 2020 08 20;52(8):790-799. Epub 2020 Jul 20.

Center for Bioinformatics and Functional Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.
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http://dx.doi.org/10.1038/s41588-020-0664-8DOI Listing
August 2020

Quantifying genetic effects on disease mediated by assayed gene expression levels.

Nat Genet 2020 06 18;52(6):626-633. Epub 2020 May 18.

Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.

Disease variants identified by genome-wide association studies (GWAS) tend to overlap with expression quantitative trait loci (eQTLs), but it remains unclear whether this overlap is driven by gene expression levels 'mediating' genetic effects on disease. Here, we introduce a new method, mediated expression score regression (MESC), to estimate disease heritability mediated by the cis genetic component of gene expression levels. We applied MESC to GWAS summary statistics for 42 traits (average N = 323,000) and cis-eQTL summary statistics for 48 tissues from the Genotype-Tissue Expression (GTEx) consortium. Averaging across traits, only 11 ± 2% of heritability was mediated by assayed gene expression levels. Expression-mediated heritability was enriched in genes with evidence of selective constraint and genes with disease-appropriate annotations. Our results demonstrate that assayed bulk tissue eQTLs, although disease relevant, cannot explain the majority of disease heritability.
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http://dx.doi.org/10.1038/s41588-020-0625-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276299PMC
June 2020

Secure large-scale genome-wide association studies using homomorphic encryption.

Proc Natl Acad Sci U S A 2020 05 12;117(21):11608-11613. Epub 2020 May 12.

Duality Technologies, Inc., Newark, NJ 07103;

Genome-wide association studies (GWASs) seek to identify genetic variants associated with a trait, and have been a powerful approach for understanding complex diseases. A critical challenge for GWASs has been the dependence on individual-level data that typically have strict privacy requirements, creating an urgent need for methods that preserve the individual-level privacy of participants. Here, we present a privacy-preserving framework based on several advances in homomorphic encryption and demonstrate that it can perform an accurate GWAS analysis for a real dataset of more than 25,000 individuals, keeping all individual data encrypted and requiring no user interactions. Our extrapolations show that it can evaluate GWASs of 100,000 individuals and 500,000 single-nucleotide polymorphisms (SNPs) in 5.6 h on a single server node (or in 11 min on 31 server nodes running in parallel). Our performance results are more than one order of magnitude faster than prior state-of-the-art results using secure multiparty computation, which requires continuous user interactions, with the accuracy of both solutions being similar. Our homomorphic encryption advances can also be applied to other domains where large-scale statistical analyses over encrypted data are needed.
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http://dx.doi.org/10.1073/pnas.1918257117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261120PMC
May 2020

Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer.

Nat Commun 2020 04 24;11(1):2020. Epub 2020 Apr 24.

Cedars-Sinai Women's Cancer Program at the Samuel Oschin Cancer Center, Los Angeles, CA, USA.

The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and then integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4) and ZSCAN12 (P = 0.02). CRISPR/Cas9 knockout of this enhancer induces downregulation of both genes. Globally, there is an enrichment of single nucleotide variants in active binding sites for TEAD4 (P = 6 × 10-11) and its binding partner PAX8 (P = 2×10-10), a known lineage-specific transcription factor in OC. In addition, the collection of cis REs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during OC development.
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http://dx.doi.org/10.1038/s41467-020-15951-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181647PMC
April 2020

Comparison of the Level and Mechanisms of Toxicity of Carbon Nanotubes, Carbon Nanofibers, and Silicon Nanotubes in Bioassay with Four Marine Microalgae.

Nanomaterials (Basel) 2020 Mar 8;10(3). Epub 2020 Mar 8.

Far Eastern Federal University, Sukhanova 8, 690950 Vladivostok, Russian.

Nanoparticles (NPs) have various applications in medicine, cosmetics, optics, catalysis, environmental purification, and other areas nowadays. With an increasing annual production of NPs, the risks of their harmful influence to the environment and human health is rising. Currently, our knowledge about the mechanisms of interaction between NPs and living organisms is limited. Additionally, poor understanding of how physical and chemical characteristic and different conditions influence the toxicity of NPs restrict our attempts to develop the standards and regulations which might allow us to maintain safe living conditions. The marine species and their habitat environment are under continuous stress due to anthropogenic activities which result in the appearance of NPs in the aquatic environment. Our study aimed to evaluate and compare biochemical effects caused by the influence of different types of carbon nanotubes, carbon nanofibers, and silica nanotubes on four marine microalgae species. We evaluated the changes in growth-rate, esterase activity, membrane polarization, and size changes of microalgae cells using flow cytometry method. Our results demonstrated that toxic effects caused by the carbon nanotubes strongly correlated with the content of heavy metal impurities in the NPs. More hydrophobic carbon NPs with less ordered structure had a higher impact on the red microalgae because of higher adherence between the particles and mucous covering of the algae. Silica NPs caused significant inhibition of microalgae growth-rate predominantly produced by mechanical influence.
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http://dx.doi.org/10.3390/nano10030485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153241PMC
March 2020

Germline Features Associated with Immune Infiltration in Solid Tumors.

Cell Rep 2020 03;30(9):2900-2908.e4

Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA; Department of Ecology and Evolutionary Biology, Brown University, Providence, RI 02912, USA. Electronic address:

The immune composition of the tumor microenvironment influences response and resistance to immunotherapies. While numerous studies have identified somatic correlates of immune infiltration, germline features that associate with immune infiltrates in cancers remain incompletely characterized. We analyze seven million autosomal germline variants in the TCGA cohort and test for association with established immune-related phenotypes that describe the tumor immune microenvironment. We identify one SNP associated with the amount of infiltrating follicular helper T cells; 23 candidate genes, some of which are involved in cytokine-mediated signaling and others containing cancer-risk SNPs; and networks with genes that are part of the DNA repair and transcription elongation pathways. In addition, we find a positive association between polygenic risk for rheumatoid arthritis and amount of infiltrating CD8 T cells. Overall, we identify multiple germline genetic features associated with tumor-immune phenotypes and develop a framework for probing inherited features that contribute to differences in immune infiltration.
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http://dx.doi.org/10.1016/j.celrep.2020.02.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082123PMC
March 2020

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Genet Epidemiol 2020 07 1;44(5):442-468. Epub 2020 Mar 1.

Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
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http://dx.doi.org/10.1002/gepi.22288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987299PMC
July 2020

Allele-Specific QTL Fine Mapping with PLASMA.

Am J Hum Genet 2020 02 30;106(2):170-187. Epub 2020 Jan 30.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Brigham & Women's Hospital, Division of Genetics, Boston, MA 02215, USA. Electronic address:

Although quantitative trait locus (QTL) associations have been identified for many molecular traits such as gene expression, it remains challenging to distinguish the causal nucleotide from nearby variants. In addition to traditional QTLs by association, allele-specific (AS) QTLs are a powerful measure of cis-regulation that are concordant with traditional QTLs but typically less susceptible to technical/environmental noise. However, existing methods for estimating causal variant probabilities (i.e., fine mapping) cannot produce valid estimates from asQTL signals due to complexities in linkage disequilibrium (LD). We introduce PLASMA (Population Allele-Specific Mapping), a fine-mapping method that integrates QTL and asQTL information to improve accuracy. In simulations, PLASMA accurately prioritizes causal variants over a wide range of genetic architectures. Applied to RNA-seq data from 524 kidney tumor samples, PLASMA achieves a greater power at 50 samples than conventional QTL-based fine mapping at 500 samples, with more than 17% of loci fine mapped to within five causal variants, compared to 2% by QTL-based fine mapping, and a 6.9-fold overall reduction in median credible set size compared to QTL-based fine mapping when applied to H3K27AC ChIP-seq from just 28 prostate tumor/normal samples. Variants in the PLASMA credible sets for RNA-seq and ChIP-seq were enriched for open chromatin and chromatin looping, respectively, at a comparable or greater degree than credible variants from existing methods while containing far fewer markers. Our results demonstrate how integrating AS activity can substantially improve the detection of causal variants from existing molecular data.
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http://dx.doi.org/10.1016/j.ajhg.2019.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011109PMC
February 2020

Neutrophil activation by Escherichia coli isolates from human intestine: effects of bacterial hydroperoxidase activity and surface hydrophobicity.

FEBS Open Bio 2020 03 5;10(3):414-426. Epub 2020 Feb 5.

Federal Research and Clinical Center of Physical-Chemical Medicine of FMBA, Moscow, Russia.

Successful colonization of the intestine requires that bacteria interact with the innate immune system and, in particular, neutrophils. Progression of inflammatory bowel diseases (IBD) is associated with alterations in gut microbiota, and dysbiosis in Crohn's disease (CD) patients is often associated with an expansion of Escherichia coli. Here, we investigated the ability of such E. coli isolates to avoid neutrophil activation and to utilize reactive oxygen species. Neutrophil activation was detected in vitro in normal human blood via luminol chemiluminescence (CL) induced by reactive oxygen and halogen species generated by neutrophils. No significant difference in neutrophil activation in vitro was detected between isolates from inflamed (23 isolates) vs healthy intestines (5 isolates), with 10-fold variation within both groups (2.9-61.2 mV). CL activity of isolates from the same patient differed by 1.5-5 times. Twenty-four isolates from ileal aspirate, biopsy, and feces of seven patients with CD and one patient with no intestine inflammation were tested for extracellular peroxidase and catalase activity and cell surface hydrophobicity. Average values between patients varied from 26 ± 3 to 73 ± 18 µmol·g of air dry weight for peroxidase activity, from 15 ± 2 to 189 ± 56 mmol·g of air dry weight for catalase activity, and from 5 ± 3 to 105 ± 9 a.u. for the hydrophobic probe fluorescence. Extracellular peroxidase activity and hydrophobicity of bacterial cell surface correlated negatively with stimulated neutrophil CL. The ability of some isolates to avoid neutrophil activation and to utilize reactive oxygen species may provide a strategy to survive assault by the innate immune system.
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http://dx.doi.org/10.1002/2211-5463.12796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050253PMC
March 2020

Fluorouracil neutrophil extracellular traps formation inhibited by polymer nanoparticle shielding.

Mater Sci Eng C Mater Biol Appl 2020 Mar 2;108:110382. Epub 2019 Nov 2.

Laboratory of Toxicology, Medical School, University of Crete, Voutes, Heraklion Crete, 71003, Greece.

Venous thromboembolism is a frequent complication occurring in patients suffering from neoplastic diseases. Since neutrophil extracellular traps (NETs) play an important role both in the development of the tumor growth process and in inducing complications such as thrombosis, indubitably the investigation of the effect of antitumor drugs on the formation of neutrophil extracellular traps and on the ability of such drugs to prevent NETs contribution on carcinogenesis is of great interest. In the present work we studied the effect of 5-fluorouracil (5FU) and its shielded -by amphiphilic poly-N-vinylpyrrolidone (Amph-PVP) nanoparticles-nanoscaled polymeric form on the activation of human neutrophils under ex vivo conditions. Free 5FU at concentrations varying from 0.01 to 10 mg/ml was found to cause a significant (two to three times) and rapid (after 20 min) increase in the total amount of NETs in the blood. Importantly, when 5FU-loaded Amph-PVP nanoparticles were studied under the same conditions, the appearance of NETs in the blood was completely blocked providing strong evidence of their potential as delivery system for 5FU in antitumor therapy.
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http://dx.doi.org/10.1016/j.msec.2019.110382DOI Listing
March 2020

Mucin adsorbed by E. coli can affect neutrophil activation in vitro.

FEBS Open Bio 2020 02 19;10(2):180-196. Epub 2019 Dec 19.

Federal Research and Clinical Center of Physical-Chemical Medicine, Moscow, Russia.

Bacteria colonizing human intestine adhere to the gut mucosa and avoid the innate immune system. We previously demonstrated that Escherichia coli isolates can adsorb mucin from a diluted solution in vitro. Here, we evaluated the effect of mucin adsorption by E. coli cells on neutrophil activation in vitro. Activation was evaluated based on the detection of reactive oxygen species production by a chemiluminescent reaction (ChL), observation of morphological alterations in neutrophils and detection of exocytosis of myeloperoxidase and lactoferrin. We report that mucin adsorbed by cells of SharL1 isolate from Crohn's disease patient's inflamed ileum suppressed the potential for the activation of neutrophils in whole blood. Also, the binding of plasma complement proteins and immunoglobulins to the bacteria was reduced. Desialylated mucin, despite having the same adsorption efficiency to bacteria, had no effect on the blood ChL response. The effect of mucin suggests that it shields epitopes that interact with neutrophils and plasma proteins on the bacterial outer membrane. Potential candidates for these epitopes were identified among the proteins within the bacterial outer membrane fraction by 2D-PAGE, fluorescent mucin binding on a blot and HPLC-MS/MS. In vitro, the following proteins demonstrated mucin adsorption: outer membrane porins (OmpA, OmpC, OmpD and OmpF), adhesin OmpX, the membrane assembly factor OmpW, cobalamine transporter, ferrum uptake protein and the elongation factor Ef Tu-1. In addition to their other functions, these proteins are known to be bacterial surface antigens. Therefore, the shielding of epitopes by mucin may affect the dynamics and intensity of an immune response.
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http://dx.doi.org/10.1002/2211-5463.12770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996330PMC
February 2020

Medium-Dependent Antibacterial Properties and Bacterial Filtration Ability of Reduced Graphene Oxide.

Nanomaterials (Basel) 2019 Oct 13;9(10). Epub 2019 Oct 13.

Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.

Toxicity of reduced graphene oxide (rGO) has been a topic of multiple studies and was shown to depend on a variety of characteristics of rGO and biological objects of interest. In this paper, we demonstrate that when studying the same dispersions of rGO and fluorescent () bacteria, the outcome of nanotoxicity experiments also depends on the type of culture medium. We show that rGO inhibits the growth of bacteria in a nutrition medium but shows little effect on the behavior of in a physiological saline solution. The observed effects of rGO on in different media could be at least partially rationalized through the adsorption of bacteria and nutrients on the dispersed rGO sheets, which is likely mediated via hydrogen bonding. We also found that the interaction between rGO and is medium-dependent, and in physiological saline solutions they form stable flocculate structures that were not observed in nutrition media. Furthermore, the aggregation of rGO and in saline media was observed regardless of whether the bacteria were alive or dead. Filtration of the aggregate suspensions led to nearly complete removal of bacteria from filtered liquids, which highlights the potential of rGO for the filtration and separation of biological contaminants, regardless of whether they include live or dead microorganisms.
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http://dx.doi.org/10.3390/nano9101454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835404PMC
October 2019
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