Aripiprazole as a Candidate Treatment of COVID-19 Identified Through Genomic Analysis

Background: Antipsychotics modulate expression of inflammatory cytokines and inducible inflammatory enzymes. Elopiprazole (a phenylpiperazine antipsychotic drug in phase 1) has been characterized as a therapeutic drug to treat SARS-CoV-2 infection in a repurposing study. We aim to investigate the potential effects of aripiprazole (an FDA approved phenylpiperazine) on COVID-19-related immunological parameters.Methods: Differential gene expression profiles of non-COVID-19 vs. COVID-19 RNA-Seq samples (CRA002390 project in GSA database) and drug-naïve patients with non-affective psychosis at baseline and after three months of aripiprazole treatment were identified. An integrative transcriptomic analyses of aripiprazole effects on differentially expressed genes in COVID-19 patients was performed.Findings: 82 out the 377 genes (21.7%) with expression significantly altered by aripiprazole have also their expression altered in COVID-19 patients and in 93.9% of these genes their expression is reverted by aripiprazole. The number of common genes with expression altered in both analyses is significantly higher than expected (Fisher’s Exact Test, two tail; p value = 3.2e-11). 11 KEGG pathways were significantly enriched with genes with altered expression both in COVID-19 patients and aripiprazole medicated non-affective psychosis patients (p adj<0.05). The most significant pathways were associated to immune responses and mechanisms of hyperinflammation-driven pathology (i.e.,“inflammatory bowel disease (IBD)” (the most significant pathway with a p adj of 0.00021), “Th1 and Th2 cell differentiation” and “B cell receptor signaling pathway”) that have been also associated with COVID19 clinical outcome.Interpretation: This exploratory investigation may provide further support to the notion that a protective effect is exerted by aripiprazole (phenylpiperazine) by modulating the expression of genes that have shown to be altered in COVID-19 patients. Along with many ongoing studies and clinical trials, repurposing available medications could be of use in countering SARS-CoV-2 infection, but require further studies and trials.

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Aripiprazole as a candidate treatment of COVID-19 identified through genomic analysis

10.1101/2020.12.05.20244590 ◽

2020 ◽

Author(s):

Benedicto Crespo-Facorro ◽

Miguel Ruiz-Veguilla ◽

Javier Vazquez-Bourgon ◽

Ana C. Sanchez-Hidalgo ◽

Nathalia Garrido-Torres ◽

...

Keyword(s):

Expression Profiles ◽

Phase 1 ◽

Gene Expression Profiles ◽

Genomic Analysis ◽

Cell Receptor ◽

Therapeutic Drug ◽

P Value ◽

Immunological Parameters ◽

Altered Expression ◽

Exact Test

Background: Antipsychotics suppress expression of inflammatory cytokines and inducible inflammatory enzymes. Elopiprazole (a phenylpiperazine antipsychotic drug in phase 1) has been characterized as a therapeutic drug to treat SARS-CoV-2 infection in a repurposing study. We aim to investigate the potential effects of aripiprazole (an FDA approved phenylpiperazine) on COVID19-related immunological parameters. Methods: Differential gene expression profiles of non-COVID versus COVID RNA-Seq samples (CRA002390 project in GSA database) and drug-naive patients with psychosis at baseline and after three months of aripiprazole treatment was identified. An integrative analysis between COVID and aripiprazole immunomodulatory antagonist effects was performed. Findings: 82 out the 377 genes (21.7%) with expression significantly altered by aripiprazole have also their expression altered in COVID-19 patients and in 93.9% of these genes their expression is reverted by aripiprazole. The number of common genes with expression altered in both analyses is significantly higher than expected (Fisher's Exact Test, two tail; P value=3.2e-11). 11 KEGG pathways were significantly enriched with genes with altered expression both in COVID-19 patients and aripiprazole medicated schizophrenia patients (P adj<0.05). The most significant pathways were associated to the immune system such as the inflammatory bowel disease (IBD) (the most significant pathway with a P adj of 0.00021), Th1 and Th2 cell differentiation and B cell receptor signaling pathway, all three related to the defense against infections. Interpretation: This exploratory investigation may provide further support to the notion that protective effect is exerted by phenylpiperazine by modulating the immunological dysregulation associated to COVID-19. Along with many ongoing studies and clinical trials, repurposing available medications could be of use in countering SARS-CoV-2 infection, but require further studies and trials.

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Integrated Genomic Analysis of Sézary Syndrome

Genetics Research International ◽

10.4061/2011/980150 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Xin Mao ◽

Tracy Chaplin ◽

Bryan D. Young

Keyword(s):

Copy Number ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Genomic Analysis ◽

Gene Clusters ◽

Sézary Syndrome ◽

Sezary Syndrome ◽

Snp Microarray ◽

The Impact ◽

Chromosome Regions

Sézary syndrome (SS) is a rare variant of primary cutaneous T-cell lymphoma. Little is known about the underlying pathogenesis of S. To address this issue, we used Affymetrix 10K SNP microarray to analyse 13 DNA samples isolated from 8 SS patients and qPCR with ABI TaqMan SNP genotyping assays for the validation of the SNP microarray results. In addition, we tested the impact of SNP loss of heterozygosity (LOH) identified in SS cases on the gene expression profiles of SS cases detected with Affymetrix GeneChip U133A. The results showed: (1) frequent SNP copy number change and LOH involving 1, 2p, 3, 4q, 5q, 6, 7p, 8, 9, 10, 11, 12q, 13, 14, 16q, 17, and 20, (2) reduced SNP copy number at FAT gene (4q35) in 75% of SS cases, and (3) the separation of all SS cases from normal control samples by SNP LOH gene clusters at chromosome regions of 9q31q34, 10p11q26, and 13q11q12. These findings provide some intriguing information for our current understanding of the molecular pathogenesis of this tumour and suggest the possibility of presence of functional SNP LOH in SS tumour cells.

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Integrative Genomics with Mediation Analysis in a Survival Context

Computational and Mathematical Methods in Medicine ◽

10.1155/2013/413783 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Szilárd Nemes ◽

Toshima Z. Parris ◽

Anna Danielsson ◽

Zakaria Einbeigi ◽

Gunnar Steineck ◽

...

Keyword(s):

Expression Profiles ◽

Gene Expression Profiles ◽

Genomic Analysis ◽

Mrna Levels ◽

Integrative Genomics ◽

Asymptotic Results ◽

Data Set ◽

Cancer Data ◽

Dna And Rna ◽

Altered Gene

DNA copy number aberrations (DCNA) and subsequent altered gene expression profiles may have a major impact on tumor initiation, on development, and eventually on recurrence and cancer-specific mortality. However, most methods employed in integrative genomic analysis of the two biological levels, DNA and RNA, do not consider survival time. In the present note, we propose the adoption of a survival analysis-based framework for the integrative analysis of DCNA and mRNA levels to reveal their implication on patient clinical outcome with the prerequisite that the effect of DCNA on survival is mediated by mRNA levels. The specific aim of the paper is to offer a feasible framework to test the DCNA-mRNA-survival pathway. We provide statistical inference algorithms for mediation based on asymptotic results. Furthermore, we illustrate the applicability of the method in an integrative genomic analysis setting by using a breast cancer data set consisting of 141 invasive breast tumors. In addition, we provide implementation in R.

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Dose-response relationships in gene expression profiles in a harbor seal B lymphoma cell line exposed to 17α-ethinyl estradiol

Journal of Xenobiotics ◽

10.4081/xeno.2017.6702 ◽

2017 ◽

Vol 7 (1) ◽

Author(s):

Christine Kleinert ◽

Matthieu Blanchet ◽

François Gagné ◽

Michel Fournier

Keyword(s):

Gene Expression ◽

Cell Line ◽

Ethinyl Estradiol ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Harbor Seal ◽

Lymphoma Cell ◽

Lymphoma Cell Line ◽

Altered Expression ◽

B Lymphoma

The determination of changes in gene expression profiles with xenobiotic dose will allow identifying biomarkers and modes of toxicant action. The harbor seal (Phoca vitulina) 11B7501 B lymphoma cell line was exposed to 1, 10, 100, 1000, 10,000, or 25,000 μg/L 17α-ethinyl estradiol (EE2, the active compound of the contraceptive pill) for 24 h. Following exposure, RNA was extracted and transformed into cDNA. Transcript expression in exposed vs. control lymphocytes was analyzed via RT-qPCR to identify genes with altered expression. Our analysis indicates that gene expression for all but the reference gene varied with dose, suggesting that different doses induce distinct physiological responses. These findings demonstrate that RT-qPCR could be used to identify immunotoxicity and relative dose in harbor seal leukocytes.

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Single-cell immune repertoire and transcriptome sequencing reveals that clonally expanded and transcriptionally distinct lymphocytes populate the aged central nervous system in mice

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2020.2793 ◽

2021 ◽

Vol 288 (1945) ◽

pp. 20202793

Author(s):

Alexander Yermanos ◽

Daniel Neumeier ◽

Ioana Sandu ◽

Mariana Borsa ◽

Ann Cathrin Waindok ◽

...

Keyword(s):

Gene Expression ◽

Central Nervous System ◽

Nervous System ◽

B Cells ◽

Single Cell ◽

Somatic Hypermutation ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cell Receptor ◽

The Central Nervous System

Neuroinflammation plays a crucial role during ageing and various neurological conditions, including Alzheimer's disease, multiple sclerosis and infection. Technical limitations, however, have prevented an integrative analysis of how lymphocyte immune receptor repertoires and their accompanying transcriptional states change with age in the central nervous system. Here, we leveraged single-cell sequencing to simultaneously profile B cell receptor and T cell receptor repertoires and accompanying gene expression profiles in young and old mouse brains. We observed the presence of clonally expanded B and T cells in the central nervous system of aged male mice. Furthermore, many of these B cells were of the IgM and IgD isotypes, and had low levels of somatic hypermutation. Integrating gene expression information additionally revealed distinct transcriptional profiles of these clonally expanded lymphocytes. Our findings implicate that clonally related T and B cells in the CNS of elderly mice may contribute to neuroinflammation accompanying homeostatic ageing.

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Fusarium verticillioides FvPex8 is a key component of peroxisomal docking/translocation module that serves important roles in fumonisin biosynthesis but not in virulence

10.1101/2020.05.06.081687 ◽

2020 ◽

Author(s):

Wenying Yu ◽

Mei Lin ◽

Minghui Peng ◽

Huijuan Yan ◽

Jie Zhou ◽

...

Keyword(s):

Expression Profiles ◽

Fusarium Verticillioides ◽

Fumonisin B1 ◽

Gene Expression Profiles ◽

Deletion Mutants ◽

Altered Expression ◽

The Core ◽

Metabolic Functions ◽

Peroxisome Membrane

AbstractPeroxisomes are ubiquitous organelles in eukaryotic cells that fulfill various important metabolic functions. In this study, we investigated the role of Docking/Translocation Module (DTM) peroxins, mainly FvPex8, FvPex13, FvPex14, and FvPex33, in Fusarium verticillioides virulence and fumonisin B1 (FB1) biosynthesis. Protein interaction experiments suggested that FvPex13 serves as the core subunit of F. verticillioides DTM. When we generated gene deletion mutants (ΔFvpex8, ΔFvpex13, ΔFvpex14, ΔFvpex33, ΔFvpex33/14) and examined whether the expression of other peroxin genes were affected in the DTM mutants, ΔFvpex8 strain showed most drastic changes to PEX gene expression profiles. Deletion mutants exhibited disparity in carbon source utilization and defect in cell wall integrity when stress agents were applied. Under nutrient starvation, mutants also showed higher levels of lipid droplet accumulation. Notably, ΔFvpex8 mutant showed significant FB1 reduction and altered expression of FUM1 and FUM19 genes. However, FvPex13 was primarily responsible for virulence, while ΔFvpex33/14 double mutant also showed virulence defect. In summary, our study suggests that FvPex13 is the core component of DTM, regulating peroxisome membrane biogenesis as well as PTS1- and PTS2-mediated transmembrane cargo transportation. Importantly, we predict FvPex8 as a key component in DTM that affects peroxisome function in FB1 biosynthesis in F. verticillioides.

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In Silico Discovery of Candidate Drugs against Covid-19

Viruses ◽

10.3390/v12040404 ◽

2020 ◽

Vol 12 (4) ◽

pp. 404 ◽

Cited By ~ 42

Author(s):

Claudia Cava ◽

Gloria Bertoli ◽

Isabella Castiglioni

Keyword(s):

Gene Expression ◽

In Silico ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Interaction Network ◽

Enrichment Analysis ◽

Basic Mechanism ◽

Cell Receptor ◽

The Cancer Genome Atlas ◽

Pathway Enrichment Analysis

Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of ACE2 in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of ACE2-correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with ACE2. Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with ACE2 are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.

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ATIM-27. TUMOR MUTATIONAL BURDEN PREDICTS RESPONSE TO ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) IN MALIGNANT GLIOMA PATIENTS: ASSESSMENT OF TRANSCRIPTIONAL AND IMMUNOLOGICAL CORRELATES

Neuro-Oncology ◽

10.1093/neuonc/noz175.026 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi7-vi7 ◽

Cited By ~ 2

Author(s):

Matthias Gromeier ◽

Michael Brown ◽

Nike Beuabier ◽

Hai Yan ◽

Yiping He ◽

...

Keyword(s):

Flow Cytometry ◽

Immune Cell ◽

Expression Profiles ◽

Phase 1 ◽

Internal Ribosomal Entry Site ◽

Gene Expression Profiles ◽

Oral Poliovirus Vaccine ◽

Post Treatment ◽

Entry Site ◽

Biopsy Material

Abstract BACKGROUND The live attenuated oral poliovirus vaccine was modified to contain a heterologous internal ribosomal entry site stemming from human rhinovirus type 2, creating PVSRIPO. PVSRIPO recognizes CD155, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We have previously reported that deep sequencing of biopsy material obtained prior to PVSRIPO infusion confirmed that a very low mutational load is associated with longer survival. METHODS Patient tumor material from both phase I and 2 clinical trials was collected pre PVSRIPO. When available, post-treatment tissue from longitudinal samples were also collected. Tissue was subjected to RNA sequencing, histological analysis, and flow cytometry analysis. RNAseq analyses were performed comparing pre- and post- treatment expression profiles and computational predictions of tumor immune composition deciphered changes after PVSRIPO therapy. Histology and flow cytometry quantitated myeloid, CD8/4/regulatory T cell densities, and other immune cell types after treatment and compared to baseline tissue similarly analyzed to detect changes. RESULTS To date, analysis of phase 1 trial data has demonstrated a correlation between low TMB and increased markers of immunological gene expression profiles. This trend was not observed in TCGA samples that were almost exclusively primary GBM suggesting and interplay with prior therapy or evolution with recurrence. CONCLUSION Our findings presented here suggest that response to PVSRIPO therapy, and possibly that of other modalities engaging innate antiviral signatures in situ, may be dependent upon prevailing tumor microenvironment composition/status at the time of treatment.

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Molecular Determinants of Lymph Node Microenvironment Induced Host Immune Tolerance In CLL: Role for CAV1, PTPN6, and PKCβ In the Process

Blood ◽

10.1182/blood.v116.21.1367.1367 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1367-1367

Author(s):

Christine Gilling ◽

Amit Mittal ◽

Vincent Nganga ◽

Vicky Palmer ◽

Dennis D. Weisenburger ◽

...

Keyword(s):

Gene Expression ◽

Mouse Model ◽

Immune Tolerance ◽

Conflicts Of Interest ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cell Receptor ◽

Differentially Expressed ◽

Expression Levels ◽

Aggressive Disease

Abstract Abstract 1367 Previously, we have shown that gene expression profiles (GEP) of CLL cells from lymph nodes (LN), bone marrow (BM), and peripheral blood (PB) are significantly different from each other. Among the major pathways associated with differential gene expression, a “tolerogenic signature” involved in host immune tolerance is significant in regulating CLL progression. The genes associated with the tolerogenic signature are significantly differentially expressed in patient LN-CLL compared to BM-CLL and PB-CLL, suggesting that LN-CLL cells induce this immune tolerance. From 83 differentially expressed genes identified by GEP that are associated with immune dysregulation, we selected eleven genes (CAV1, PTPN6, PKCb, ZWINT, IL2Ra, CBLC, CDC42, ZNF175, ZNF264, IL10, and HLA-G) for validation studies to determine whether these genes are also dysregulated in the Emu-TCL1 mouse model of CLL. The results demonstrate a trend of upregulation of these genes as determined by qRT-PCR in the LN-tumor microenvironment. To further evaluate the kinetics of selected gene expression during tumor progression, we determined the expression levels of Cav1, Ptpn6, and Pkcb at 12, 24, and 36 weeks of CLL development in the Em-TCL1 mouse model. We found that the expression of all three genes increased as a function of age, indicating a correlation of gene expression with disease progression. In addition, as CLL progressed in these mice there was a marked decrease in CD4+ and CD8+ T cells. The murine data were further validated using CLL cells from the same patients with indolent versus aggressive disease indicating a similar trend in expression as CLL progressed (n=4). Furthermore, patient data analyzed by Kaplan Meier analyses of the expression levels of the selected genes indicated a significant association between down-regulation of PTPN6 (p=0.031) and up-regulation of ZWINT (p<0.001) with clinical outcome as determined by a shorter time to treatment (p<0.05). Functional analysis by knockdown of CAV1 and PKCb in primary patient CLL cells determined by MTT assay showed a decrease in proliferation following knockdown of these genes (p<0.005). Protein-interaction modeling revealed regulation of CAV1 and PTPN6 by one another. Additionally, the PTPN6 protein regulates B cell receptor (BCR) signaling and subsequently the BCR regulates PKCb. Therefore, these data from both mice and humans with CLL, argue that an aggressive disease phenotype is paralleled by expression of genes associated with immune suppression. In particular, evidence presented here suggests, dysregulation of CAV1, PTPN6, ZWINT, and PKCb expression promotes CLL progression. Disclosures: No relevant conflicts of interest to declare.

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Single-cell intracellular epitope and transcript detection revealing signal transduction dynamics

10.1101/2020.12.02.408120 ◽

2020 ◽

Author(s):

Francesca Rivello ◽

Erik van Buijtenen ◽

Kinga Matuła ◽

Jessie A.G.L. van Buggenum ◽

Paul Vink ◽

...

Keyword(s):

Signal Transduction ◽

Single Cell ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cell Receptor ◽

B Cell Receptor ◽

Protein Levels ◽

Inhibitory Drug ◽

Insight Into ◽

Transcript Detection

AbstractCurrent high-throughput single-cell multi-omics methods cannot concurrently map changes in (phospho)protein levels and the associated gene expression profiles. We present QuRIE-seq (Quantification of RNA and Intracellular Epitopes by sequencing) and use multi-factor omics analysis (MOFA+) to map signal transduction over multiple timescales. We demonstrate that QuRIE-seq can trace the activation of the B-cell receptor pathway at the minute and hour time-scale and provide insight into the mechanism of action of an inhibitory drug, Ibrutinib.

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