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Article ; Online: Pharmacogenetic Gene-Drug Associations in Pediatric Burn and Surgery Patients.

Grimsrud, Kristin N / Davis, Ryan R / Tepper, Clifford G / Palmieri, Tina L

Journal of burn care & research : official publication of the American Burn Association

2022 Volume 43, Issue 5, Page(s) 987–996

Abstract: Management of critically ill patients requires simultaneous administration of many medications. Treatment for patient comorbidities may lead to drug-drug interactions which decrease drug efficacy or increase adverse reactions. Current practices rely on a ...

Abstract	Management of critically ill patients requires simultaneous administration of many medications. Treatment for patient comorbidities may lead to drug-drug interactions which decrease drug efficacy or increase adverse reactions. Current practices rely on a one-size-fits-all dosing approach. Pharmacogenetic testing is generally reserved for addressing problems rather than used proactively to optimize care. We hypothesized that burn and surgery patients will have one or more genetic variants in drug metabolizing pathways used by one or more medications administered during the patient's hospitalization. The aim of this study was to determine the frequency of variants with abnormal function in the primary drug pathways and identify which medications may be impacted. Genetic (19 whole exome and 11 whole genome) and medication data from 30 pediatric burn and surgery patients were analyzed to identify pharmacogene-drug associations. Nineteen patients were identified with predicted altered function in one or more of the following genes: CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The majority had decreased function, except for several patients with CYP2C19 rapid or ultrarapid variants. Some drugs administered during hospitalization that rely on these pathways include hydrocodone, oxycodone, methadone, ibuprofen, ketorolac, celecoxib, diazepam, famotidine, diphenhydramine, and glycopyrrolate. Approximately one-third of the patients tested had functionally impactful genotypes in each of the primary drug metabolizing pathways. This study suggests that genetic variants may in part explain the vast variability in drug efficacy and suggests that future pharmacogenetics research may optimize dosing regimens.
MeSH term(s)	Burns/drug therapy ; Burns/genetics ; Burns/surgery ; Child ; Cytochrome P-450 CYP2C19/genetics ; Genotype ; Humans ; Pharmaceutical Preparations ; Pharmacogenetics ; Pharmacogenomic Testing
Chemical Substances	Pharmaceutical Preparations ; Cytochrome P-450 CYP2C19 (EC 1.14.14.1)
Language	English
Publishing date	2022-05-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2224246-6
ISSN	1559-0488 ; 1559-047X
ISSN (online)	1559-0488
ISSN	1559-047X
DOI	10.1093/jbcr/irac062
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Virally encoded interleukin-6 facilitates KSHV replication in monocytes and induction of dysfunctional macrophages.

Shimoda, Michiko / Inagaki, Tomoki / Davis, Ryan R / Merleev, Alexander / Tepper, Clifford G / Maverakis, Emanual / Izumiya, Yoshihiro

PLoS pathogens

2023 Volume 19, Issue 10, Page(s) e1011703

Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi's sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected ... ...

Abstract	Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi's sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected cell population is crucial for curing KSHV-associated diseases. Using scRNA-seq, we demonstrate that KSHV preferentially infects CD14+ monocytes, sustains viral lytic replication through the viral interleukin-6 (vIL-6), which activates STAT1 and 3, and induces an inflammatory gene expression program. To study the role of vIL-6 in monocytes upon KSHV infection, we generated recombinant KSHV with premature stop codon (vIL-6(-)) and its revertant viruses (vIL-6(+)). Infection of the recombinant viruses shows that both vIL-6(+) and vIL-6(-) KSHV infection induced indistinguishable host anti-viral response with STAT1 and 3 activations in monocytes; however, vIL-6(+), but not vIL-6(-), KSHV infection promoted the proliferation and differentiation of KSHV-infected monocytes into macrophages. The macrophages derived from vIL-6(+) KSHV infection showed a distinct transcriptional profile of elevated IFN-pathway activation with immune suppression and were compromised in T-cell stimulation function compared to those from vIL-6(-) KSHV infection or uninfected control. Notably, a viral nuclear long noncoding RNA (PAN RNA), which is required for sustaining KSHV gene expression, was substantially reduced in infected primary monocytes upon vIL-6(-) KSHV infection. These results highlight the critical role of vIL-6 in sustaining KSHV transcription in primary monocytes. Our findings also imply a clever strategy in which KSHV utilizes vIL-6 to secure its viral pool by expanding infected monocytes via differentiating into longer-lived dysfunctional macrophages. This mechanism may facilitate KSHV to escape from host immune surveillance and to support a lifelong infection.
MeSH term(s)	Humans ; Herpesvirus 8, Human/physiology ; Interleukin-6/metabolism ; Monocytes/metabolism ; Sarcoma, Kaposi ; Herpesviridae Infections/metabolism ; Macrophages/metabolism ; Immunologic Factors/metabolism ; Virus Replication
Chemical Substances	Interleukin-6 ; Immunologic Factors
Language	English
Publishing date	2023-10-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011703
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Article: KSHV uses viral IL6 to expand infected immunosuppressive macrophages.

Shimoda, Michiko / Inagaki, Tomoki / Davis, Ryan R / Merleev, Alexander / Tepper, Clifford G / Maverakis, Emanual / Izumiya, Yoshihiro

bioRxiv : the preprint server for biology

2023

Abstract	Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi's sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected cell population is crucial for curing KSHV-associated diseases. Here we demonstrate that KSHV preferentially infects CD14 Summary: KSHV causes multiple inflammatory diseases, however, the underlying mechanism is not clear. Shimoda et al. demonstrate that KSHV preferentially infects monocytes and utilizes virally encoded interleukin-6 to expand and deregulate infected monocytes. This helps the virus escape from host immune surveillance.
Language	English
Publishing date	2023-03-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.05.531224
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Article: Use of RNA-Seq and a Transgenic Mouse Model to Identify Genes Which May Contribute to Mutant p53-Driven Prostate Cancer Initiation

Vinall, Ruth / Chen, Qian / Talbott, George / Ramsamooj, Rajendra / Dang, An / Tepper, Clifford G. / Borowsky, Alexander

Biology. 2022 Jan. 29, v. 11, no. 2

2022

Abstract: We previously demonstrated that the Trp53-R270H mutation can drive prostate cancer (CaP) initiation using the FVB.129S4 (Trp53ᵗᵐ³ᵀʸʲ/ʷᵗ); FVB.129S (Nkx3-1ᵗᵐ³⁽ᶜʳᵉ⁾ᴹᵐˢʷᵗ) genetically engineered mouse model (GEM). We now validate this finding in a different ...

Abstract	We previously demonstrated that the Trp53-R270H mutation can drive prostate cancer (CaP) initiation using the FVB.129S4 (Trp53ᵗᵐ³ᵀʸʲ/ʷᵗ); FVB.129S (Nkx3-1ᵗᵐ³⁽ᶜʳᵉ⁾ᴹᵐˢʷᵗ) genetically engineered mouse model (GEM). We now validate this finding in a different model (B6.129S4-Trp53ᵗᵐ³.¹ᵀʸʲ/J mice) and use RNA-sequencing (RNA-Seq) to identify genes which may contribute to Trp53 R270H-mediated prostate carcinogenesis. Wildtype (Trp53ᵂᵀ/ᵂᵀ), heterozygous (Trp53ᴿ²⁷⁰ᴴ/ᵂᵀ), and homozygous mice (Trp53ᴿ²⁷⁰ᴴ/ᴿ²⁷⁰ᴴ) were exposed to 5 Gy irradiation to activate and stabilize p53, and thereby enhance our ability to identify differences in transcriptional activity between the three groups of mice. Mouse prostates were harvested 6 h post-irradiation and processed for histological/immunohistochemistry (IHC) analysis or were snap-frozen for RNA extraction and transcriptome profiling. IHC analyses determined that presence of the Trp53-R270H mutation impacts apoptosis (lower caspase 3 activity) but not cell proliferation (Ki67). RNA-Seq analysis identified 1378 differentially expressed genes, including wildtype p53 target genes (E.g., Cdkn1a, Bax, Bcl2, Kras, Mdm2), p53 gain-of-function (GOF)-related genes (Mgmt, Id4), and CaP-related genes (Cav-1, Raf1, Kras). Further understanding the mechanisms which contribute to prostate carcinogenesis could allow for the development of improved preventive methods, diagnostics, and treatments for CaP.
Keywords	RNA ; apoptosis ; carcinogenesis ; caspase-3 ; cell proliferation ; diagnostic techniques ; gain-of-function mutation ; gene expression regulation ; genetic engineering ; heterozygosity ; homozygosity ; immunohistochemistry ; irradiation ; mice ; mutants ; prostatic neoplasms ; sequence analysis ; transcription (genetics) ; transcriptome
Language	English
Dates of publication	2022-0129
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology11020218
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Identification of integrin drug targets for 17 solid tumor types.

Arun, Adith S / Tepper, Clifford G / Lam, Kit S

Oncotarget

2018 Volume 9, Issue 53, Page(s) 30146–30162

Abstract: Integrins are contributors to remodeling of the extracellular matrix and cell migration. Integrins participate in the assembly of the actin cytoskeleton, regulate growth factor signaling pathways, cell proliferation, and control cell motility. In solid ... ...

Abstract	Integrins are contributors to remodeling of the extracellular matrix and cell migration. Integrins participate in the assembly of the actin cytoskeleton, regulate growth factor signaling pathways, cell proliferation, and control cell motility. In solid tumors, integrins are involved in promoting metastasis to distant sites, and angiogenesis. Integrins are a key target in cancer therapy and imaging. Integrin antagonists have proven successful in halting invasion and migration of tumors. Overexpressed integrins are prime anti-cancer drug targets. To streamline the development of specific integrin cancer therapeutics, we curated data to predict which integrin heterodimers are pausible therapeutic targets against 17 different solid tumors. Computational analysis of The Cancer Genome Atlas (TCGA) gene expression data revealed a set of integrin targets that are differentially expressed in tumors. Filtered by FPKM (Fragments Per Kilobase of transcript per Million mapped reads) expression level, overexpressed subunits were paired into heterodimeric protein targets. By comparing the RNA-seq differential expression results with immunohistochemistry (IHC) data, overexpressed integrin subunits were validated. Biologics and small molecule drug compounds against these identified overexpressed subunits and heterodimeric receptors are potential therapeutics against these cancers. In addition, high-affinity and high-specificity ligands against these integrins can serve as efficient vehicles for delivery of cancer drugs, nanotherapeutics, or imaging probes against cancer.
Language	English
Publishing date	2018-07-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.25731
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Article: Use of RNA-Seq and a Transgenic Mouse Model to Identify Genes Which May Contribute to Mutant p53-Driven Prostate Cancer Initiation.

Vinall, Ruth / Chen, Qian / Talbott, George / Ramsamooj, Rajendra / Dang, An / Tepper, Clifford G / Borowsky, Alexander

Biology

2022 Volume 11, Issue 2

Abstract: We previously demonstrated that ... ...

Abstract	We previously demonstrated that the
Language	English
Publishing date	2022-01-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology11020218
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Article ; Online: KSHV Topologically Associating Domains in Latent and Reactivated Viral Chromatin.

Campbell, Mel / Chantarasrivong, Chanikarn / Yanagihashi, Yuichi / Inagaki, Tomoki / Davis, Ryan R / Nakano, Kazushi / Kumar, Ashish / Tepper, Clifford G / Izumiya, Yoshihiro

Journal of virology

2022 Volume 96, Issue 14, Page(s) e0056522

Abstract: Eukaryotic genomes are structurally organized via the formation of multiple loops that create gene expression regulatory units called topologically associating domains (TADs). Here we revealed the KSHV TAD structure at 500 bp resolution and constructed a ...

Abstract	Eukaryotic genomes are structurally organized via the formation of multiple loops that create gene expression regulatory units called topologically associating domains (TADs). Here we revealed the KSHV TAD structure at 500 bp resolution and constructed a 3D KSHV genomic structural model with 2 kb binning. The latent KSHV genome formed very similar genomic architectures in three different naturally infected PEL cell lines and in an experimentally infected epithelial cell line. The majority of the TAD boundaries were occupied by structural maintenance of chromosomes (SMC1) cohesin complex and CCCTC-binding factor (CTCF), and the KSHV transactivator was recruited to those sites during reactivation. Triggering KSHV gene expression decreased prewired genomic loops within the regulatory unit, while contacts extending outside of regulatory borders increased, leading to formation of a larger regulatory unit with a shift from repressive to active compartments (B to A). The 3D genomic structural model proposes that the immediate early promoter region is localized on the periphery of the 3D viral genome during latency, while highly inducible noncoding RNA regions moved toward the inner space of the structure, resembling the configuration of a "bird cage" during reactivation. The compartment-like properties of viral episomal chromatin structure and its reorganization during the transition from latency may help facilitate viral gene transcription.
MeSH term(s)	Chromatin/genetics ; Gene Expression Regulation, Viral ; Genome, Viral ; Herpesvirus 8, Human/genetics ; Humans ; Trans-Activators/genetics ; Virus Latency/genetics
Chemical Substances	Chromatin ; Trans-Activators
Language	English
Publishing date	2022-07-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00565-22
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Article ; Online: C-terminal tensin-like (

Chiu, Chun-Lung / Hong, Shiao-Ya / Tan, Ying / Lee, Yuh-Ru Julie / Shih, Yi-Ping / Tepper, Clifford G / Lo, Su Hao

Genes & diseases

2022 Volume 10, Issue 3, Page(s) 643–646

Language	English
Publishing date	2022-06-17
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2821806-1
ISSN	2352-3042 ; 2352-3042
ISSN (online)	2352-3042
ISSN	2352-3042
DOI	10.1016/j.gendis.2022.05.035
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Article: KSHV vIL-6 Enhances Inflammatory Responses by Epigenetic Reprogramming.

Inagaki, Tomoki / Wang, Kang-Hsin / Kumar, Ashish / Izumiya, Chie / Miura, Hiroki / Komaki, Somayeh / Davis, Ryan R / Tepper, Clifford G / Katano, Harutaka / Shimoda, Michiko / Izumiya, Yoshihiro

bioRxiv : the preprint server for biology

2023

Abstract: Kaposi sarcoma-associated herpesvirus (KSHV) inflammatory cytokine syndrome (KICS) is a newly described chronic inflammatory disease condition caused by KSHV infection and is characterized by high KSHV viral load and sustained elevations of serum KSHV- ... ...

Abstract	Kaposi sarcoma-associated herpesvirus (KSHV) inflammatory cytokine syndrome (KICS) is a newly described chronic inflammatory disease condition caused by KSHV infection and is characterized by high KSHV viral load and sustained elevations of serum KSHV-encoded IL-6 (vIL-6) and human IL-6 (hIL-6). KICS has significant immortality and possesses greater risks of having other complications, which include malignancies. Although prolonged inflammatory vIL-6 exposure by persistent KSHV infection is expected to have key roles in subsequent disease development, the biological effects of prolonged vIL-6 exposure remain elusive. Using thiol-Linked Alkylation for the Metabolic Sequencing and Cleavage Under Target & Release Using Nuclease analysis, we studied the effect of prolonged vIL-6 exposure in chromatin landscape and resulting cytokine production. The studies showed that prolonged vIL-6 exposure increased Bromodomain containing 4 (BRD4) and histone H3 lysine 27 acetylation co-occupancies on chromatin, and the recruitment sites were frequently co-localized with poised RNAPII with associated enzymes. Increased BRD4 recruitment on promoters was associated with increased and prolonged NF-κB p65 binding after the lipopolysaccharide stimulation. The p65 binding resulted in quicker and sustained transcription bursts from the promoters; this mechanism increased total amounts of hIL-6 and IL-10 in tissue culture. Pretreatment with the BRD4 inhibitor, OTX015, eliminated the enhanced inflammatory cytokine production. These findings suggest that persistent vIL-6 exposure may establish a chromatin landscape favorable for the reactivation of inflammatory responses in monocytes. This epigenetic memory may explain the greater risk of chronic inflammatory disease development in KSHV-infected individuals.
Language	English
Publishing date	2023-07-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.25.546454
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Article ; Online: KSHV vIL-6 enhances inflammatory responses by epigenetic reprogramming.

Inagaki, Tomoki / Wang, Kang-Hsin / Kumar, Ashish / Izumiya, Chie / Miura, Hiroki / Komaki, Somayeh / Davis, Ryan R / Tepper, Clifford G / Katano, Harutaka / Shimoda, Michiko / Izumiya, Yoshihiro

PLoS pathogens

2023 Volume 19, Issue 11, Page(s) e1011771

Abstract	Kaposi sarcoma-associated herpesvirus (KSHV) inflammatory cytokine syndrome (KICS) is a newly described chronic inflammatory disease condition caused by KSHV infection and is characterized by high KSHV viral load and sustained elevations of serum KSHV-encoded IL-6 (vIL-6) and human IL-6 (hIL-6). KICS has significant immortality and greater risks of other complications, including malignancies. Although prolonged inflammatory vIL-6 exposure by persistent KSHV infection is expected to have key roles in subsequent disease development, the biological effects of prolonged vIL-6 exposure remain elusive. Using thiol(SH)-linked alkylation for the metabolic (SLAM) sequencing and Cleavage Under Target & Release Using Nuclease analysis (CUT&RUN), we studied the effect of prolonged vIL-6 exposure in chromatin landscape and resulting cytokine production. The studies showed that prolonged vIL-6 exposure increased Bromodomain containing 4 (BRD4) and histone H3 lysine 27 acetylation co-occupancies on chromatin, and the recruitment sites were frequently co-localized with poised RNA polymerase II with associated enzymes. Increased BRD4 recruitment on promoters was associated with increased and prolonged NF-κB p65 binding after the lipopolysaccharide stimulation. The p65 binding resulted in quicker and sustained transcription bursts from the promoters; this mechanism increased total amounts of hIL-6 and IL-10 in tissue culture. Pretreatment with the BRD4 inhibitors, OTX015 and MZ1, eliminated the enhanced inflammatory cytokine production. These findings suggest that persistent vIL-6 exposure may establish a chromatin landscape favorable for the reactivation of inflammatory responses in monocytes. This epigenetic memory may explain the greater risk of chronic inflammatory disease development in KSHV-infected individuals.
MeSH term(s)	Humans ; Herpesvirus 8, Human/physiology ; Interleukin-6/metabolism ; Nuclear Proteins/metabolism ; Transcription Factors/metabolism ; Cytokines/metabolism ; Herpesviridae Infections/metabolism ; Chromatin/metabolism ; Epigenesis, Genetic ; Sarcoma, Kaposi ; Cell Cycle Proteins/metabolism
Chemical Substances	Interleukin-6 ; Nuclear Proteins ; Transcription Factors ; Cytokines ; Chromatin ; BRD4 protein, human ; Cell Cycle Proteins
Language	English
Publishing date	2023-11-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011771
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