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

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

Frontiers in Pharmacology ◽

10.3389/fphar.2021.646701 ◽

2021 ◽

Vol 12 ◽

Author(s):

Benedicto Crespo-Facorro ◽

Miguel Ruiz-Veguilla ◽

Javier Vázquez-Bourgon ◽

Ana C. Sánchez-Hidalgo ◽

Nathalia Garrido-Torres ◽

...

Keyword(s):

Expression Profiles ◽

Phase 1 ◽

Gene Expression Profiles ◽

Genomic Analysis ◽

Cell Receptor ◽

Therapeutic Drug ◽

Immunological Parameters ◽

Affective Psychosis ◽

Altered Expression ◽

Exact Test

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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Gene Expression Profiling of Microdissected Hodgkin Reed Sternberg Cells: Molecular Subtypes and Treatment Outcome Correlations.

Blood ◽

10.1182/blood.v114.22.268.268 ◽

2009 ◽

Vol 114 (22) ◽

pp. 268-268

Author(s):

Christian Steidl ◽

Tang Lee ◽

Pedro Farinha ◽

Adele Telenius ◽

Merrill Boyle ◽

...

Keyword(s):

Gene Expression ◽

Treatment Failure ◽

B Cell ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cell Receptor ◽

P Value ◽

Receptor Signaling ◽

Hematopoietic Progenitor ◽

Cell Receptor Signaling

Abstract Abstract 268 INTRODUCTION: Classical Hodgkin lymphoma (cHL) is unique among lymphomas due to the scarcity of the malignant Hodgkin Reed Sternberg (HRS) cells, which are derived from clonal germinal center B cells. Investigations using laser capture microdissection permit more detailed analysis of these cells. However, most recent studies were limited by low case numbers and lack of available clinical data. PATIENTS AND METHODS: We studied 29 cases of cHL and the 5 HL lines KMH2, HDLM2, L428, L540, and L1236 by gene expression profiling. All patients were treated at the BC Cancer Agency between 1984 and 2006 and received at least 4 cycles of polychemotherapy and stage-dependent radiotherapy. The cohort also included 5 biopsies taken at relapse. Treatment failure was defined as disease progression or relapse at any time (n=14) after initiation of treatment; treatment success as absence of progression (n=15). We used laser microdissection (Molecular Machines & Industries Cellcut with Nikon Eclipse TE2000-S microscope) to study the enriched HRS cell compartment separately from the microenvironment. RNA extraction was performed on pools of 1000 microdissected HRS cells in each case. Gene expression profiles were generated using Affymetrix HG UA133 2.0 Plus arrays using two-cycle labeling reactions. HRS cell profiles were compared to microdissected germinal centers (GC), and HL cell line profiles compared to enriched tonsillar CD77+ centroblasts (MACS cell separation, Miltenyi). Furthermore, we compared gene expression profiles of treatment failures to those of treatment successes. RESULTS: We identified 1342 differentially expressed probesets (fold change >5, False Discovery Rate (FDR) adjusted p value <0.001) between HRS and GC cells. Using overrepresentation analysis we found genes involved in NFκB, JAK/Stat, IL-6, IL-9 signaling, cytotoxic T lymphocyte-mediated apoptosis and IL-15 production to be significantly over-expressed in HRS cells and genes involved in B cell, T cell receptor signaling and many transcriptional regulators such as FOXO1, E2F5, IRF8, NFATC1, NFYB, POU2AF1 to be significantly under-expressed in HRS cell. Comparison of these data to differentially expressed genes in the HL cell lines (1004 genes, fold change >5, FDR-adjusted p value <0.001) showed significant overlap of genes involved in proliferation, apoptosis, IL15 signaling and B cell receptor signaling, while overrepresentation of metabolism genes was unique to the cell lines. Hierarchical clustering of all 29 primary HL cases identified 3 separate clusters characterized by 1) a cytotoxic signature, 2) TNF/TGFB receptor signaling or 3) a residual B cell signature. Dichotomizing the profiles into the two treatment outcome groups demonstrated that NFγB signaling, complement system genes and genes involved in the developmental process of hematopoietic progenitor cells, macrophages and blood vessels were overexpressed in treatment failure samples. DISCUSSION: Using microdissection of HRS cells in a large number of cases we were able to further characterize the unique expression program of HL and refine the data inventory about dysregulated cellular functions and pathways in this disease. Overexpression of genes associated with NFκB, complement and hematopoietic progenitor cells proliferation correlate strongly with treatment failure. Further study using immunohistochemistry is currently ongoing to validate these findings and to develop clinically useful biomarkers. Disclosures: Gascoyne: Roche Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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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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ATIM-06. TREATMENT OF RECURRENT/REFRACTORY (R/R) ANAPLASTIC ASTROCYTOMA (AA, WHO GRADE 3) PATIENTS WITH ANTI-TGFß2 RNA THERAPEUTIC OT-101 VERSUS TEMOZOLOMIDE IS ASSOCIATED WITH IMPROVED OVERALL SURVIVAL

Neuro-Oncology ◽

10.1093/neuonc/noz175.006 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi2-vi2

Author(s):

Fatih Uckun ◽

Sanjive Qazi ◽

David Nam ◽

Larn Hwang ◽

Vuong Trieu

Keyword(s):

Overall Survival ◽

Phase 1 ◽

Single Agent ◽

Objective Response ◽

Clinical Results ◽

P Value ◽

Convection Enhanced Delivery ◽

Chi Square ◽

Who Grade ◽

Exact Test

Abstract BACKGROUND OT-101 is a first-in-class RNA therapeutic designed to disrupt the immunosuppressive action of TGFß2. During Phase 1 clinical trials, OT-101 induced partial responses in R/R AA patients. We now report our clinical results from a randomized Phase IIB study (NCT00431561) that further evaluated its single agent activity in R/R AA patients in side-by-side comparison with the standard chemotherapy drug temozolomide (TMZ). METHODS OT-101 was administered via high-flow microperfusion with an intratumoral catheter using a convection enhanced delivery (CED) system. 26 AA patients (12: 2.5 mg/cycle; 14: 19.8 mg/cycle) received 7-day cycles of OT-101 every other week via continuous infusion for 4–11 cycles. Response determinations were based on central review of MRI scans by an independent review committee according to standard as well as modified McDonald criteria. 11 patients in the active control arm were treated with TMZ (150–200 mg/m2, 5 days/28-day cycles x up to 6 treatment cycles). Standard statistical methods were applied for the analysis of data. RESULTS 14 of 26 patients (53.8%) treated with 4–11 cycles of OT-101 had either a CR (N=2) or PR (N=12) as their best overall response. The average time until 99% reduction of their tumor volumes ranged from 9.9 to 115.4 (median: 23.7) months. In contrast, only 1 of 10 evaluable patients (10%) treated with TMZ achieved an objective response which was a PR (Fisher’s exact test, 2-tailed, P-value = 0.0002). The median overall survival (OS) was 1154 days (95% CI: 811 - >1743) for the OT-101 group and 590 days (95% CI: 287 - >1137) days for the TMZ group (Log Rank Chi Square = 7.55, P-value = 0.006). CONCLUSION Our results confirm and extend previous studies and provide early evidence that the anti-TGFß2 RNA therapeutic OT-101 is at least as active as TMZ in salvage therapy of R/R AA patients.

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