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  1. Article ; Online: Correction: Preclinical safety and biodistribution of CRISPR targeting SIV in non-human primates.

    Burdo, Tricia H / Chen, Chen / Kaminski, Rafal / Sariyer, Ilker K / Mancuso, Pietro / Donadoni, Martina / Smith, Mandy D / Sariyer, Rahsan / Caocci, Maurizio / Liao, Shuren / Liu, Hong / Huo, Wenwen / Zhao, Huaqing / Misamore, John / Lewis, Mark G / Simonyan, Vahan / Thompson, Elaine E / Xu, Ethan Y / Cradick, Thomas J /
    Gordon, Jennifer / Khalili, Kamel

    Gene therapy

    2024  

    Language English
    Publishing date 2024-01-12
    Publishing country England
    Document type Published Erratum
    ZDB-ID 1191036-7
    ISSN 1476-5462 ; 0969-7128
    ISSN (online) 1476-5462
    ISSN 0969-7128
    DOI 10.1038/s41434-023-00438-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Transmitted/founder SHIV.D replicates in the brain, causes neuropathogenesis, and persists on combination antiretroviral therapy in rhesus macaques.

    Podgorski, Rachel M / Robinson, Jake A / Smith, Mandy D / Mallick, Suvadip / Zhao, Huaqing / Veazey, Ronald S / Kolson, Dennis L / Bar, Katharine J / Burdo, Tricia H

    Retrovirology

    2023  Volume 20, Issue 1, Page(s) 13

    Abstract: A biologically relevant non-human primate (NHP) model of HIV persistence in the central nervous system (CNS) is necessary. Most current NHP/SIV models of HIV infection fail to recapitulate viral persistence in the CNS without encephalitis or fail to ... ...

    Abstract A biologically relevant non-human primate (NHP) model of HIV persistence in the central nervous system (CNS) is necessary. Most current NHP/SIV models of HIV infection fail to recapitulate viral persistence in the CNS without encephalitis or fail to employ viruses that authentically represent the ongoing HIV-1 pandemic. Here, we demonstrate viral replication in the brain and neuropathogenesis after combination antiretroviral therapy (ART) in rhesus macaques (RMs) using novel macrophage-tropic transmitted/founder (TF) simian-human immunodeficiency virus SHIV.D.191,859 (SHIV.D). Quantitative immunohistochemistry (IHC) and DNA/RNAscope in situ hybridization (ISH) were performed on three brain regions from six SHIV.D-infected RMs; two necropsied while viremic, two during analytical treatment interruptions, and two on suppressive ART. We demonstrated myeloid-mediated neuroinflammation, viral replication, and proviral DNA in the brain in all animals. These results demonstrate that TF SHIV.D models native HIV-1 CNS replication, pathogenesis, and persistence on ART in rhesus macaques.
    MeSH term(s) Animals ; Humans ; Macaca mulatta ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; HIV Infections/drug therapy ; Antiretroviral Therapy, Highly Active ; Simian Immunodeficiency Virus/genetics ; Brain ; HIV-1/genetics ; Virus Replication/physiology ; Viral Load
    Language English
    Publishing date 2023-08-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2142602-8
    ISSN 1742-4690 ; 1742-4690
    ISSN (online) 1742-4690
    ISSN 1742-4690
    DOI 10.1186/s12977-023-00628-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Increased Peripheral Inflammation Is Associated With Structural Brain Changes and Reduced Blood Flow in People With Virologically Controlled HIV.

    Burdo, Tricia H / Robinson, Jake A / Cooley, Sarah / Smith, Mandy D / Flynn, Jacqueline / Petersen, Kalen J / Nelson, Brittany / Westerhaus, Elizabeth / Wisch, Julie / Ances, Beau M

    The Journal of infectious diseases

    2023  Volume 228, Issue 8, Page(s) 1071–1079

    Abstract: Background: While antiretroviral therapy (ART) has improved outcomes for people with HIV (PWH), brain dysfunction is still evident. Immune activation and inflammation remain elevated in PWH receiving ART, thereby contributing to morbidity and mortality. ...

    Abstract Background: While antiretroviral therapy (ART) has improved outcomes for people with HIV (PWH), brain dysfunction is still evident. Immune activation and inflammation remain elevated in PWH receiving ART, thereby contributing to morbidity and mortality. Previous studies demonstrated reduced functional and structural changes in PWH; however, underlying mechanisms remain elusive.
    Methods: Our cohort consisted of PWH with ART adherence and viral suppression ( < 50 copies/mL; N = 173). Measurements included immune cell markers of overall immune health (CD4/CD8 T-cell ratio) and myeloid inflammation (CD16+ monocytes), plasma markers of inflammatory status (soluble CD163 and CD14), and structural and functional neuroimaging (volume and cerebral blood flow [CBF], respectively).
    Results: Decreased CD4/CD8 ratios correlated with reduced brain volume, and higher levels of inflammatory CD16+ monocytes were associated with reduced brain volume in total cortex and gray matter. An increase in plasma soluble CD14-a marker of acute peripheral inflammation attributed to circulating microbial products-was associated with reduced CBF within the frontal, parietal, temporal, and occipital cortices and total gray matter.
    Conclusions: CD4/CD8 ratio and number of CD16+ monocytes, which are chronic immune cell markers, are associated with volumetric loss in the brain. Additionally, this study shows a potential new association between plasma soluble CD14 and CBF.
    MeSH term(s) Humans ; Lipopolysaccharide Receptors ; HIV Infections/complications ; HIV Infections/drug therapy ; Inflammation ; Biomarkers ; Monocytes ; Brain/diagnostic imaging ; Brain/metabolism
    Chemical Substances Lipopolysaccharide Receptors ; Biomarkers
    Language English
    Publishing date 2023-07-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3019-3
    ISSN 1537-6613 ; 0022-1899
    ISSN (online) 1537-6613
    ISSN 0022-1899
    DOI 10.1093/infdis/jiad229
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  4. Article ; Online: SIV-Mediated Synaptic Dysfunction Is Associated with an Increase in Synapsin Site 1 Phosphorylation and Impaired PP2A Activity.

    Shekarabi, Masoud / Robinson, Jake A / Smith, Mandy D / Burdo, Tricia H

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2019  Volume 39, Issue 35, Page(s) 7006–7018

    Abstract: Although the reduction of viral loads in people with HIV undergoing combination antiretroviral therapy has mitigated AIDS-related symptoms, the prevalence of neurological impairments has remained unchanged. HIV-associated CNS dysfunction includes ... ...

    Abstract Although the reduction of viral loads in people with HIV undergoing combination antiretroviral therapy has mitigated AIDS-related symptoms, the prevalence of neurological impairments has remained unchanged. HIV-associated CNS dysfunction includes impairments in memory, attention, memory processing, and retrieval. Here, we show a significant site-specific increase in the phosphorylation of Syn I serine 9, site 1, in the frontal cortex lysates and synaptosome preparations of male rhesus macaques infected with simian immunodeficiency virus (SIV) but not in uninfected or SIV-infected antiretroviral therapy animals. Furthermore, we found that a lower protein phosphatase 2A (PP2A) activity, a phosphatase responsible for Syn I (S9) dephosphorylation, is primarily associated with the higher S9 phosphorylation in the frontal cortex of SIV-infected macaques. Comparison of brain sections confirmed higher Syn I (S9) in the frontal cortex and greater coexpression of Syn I and PP2A A subunit, which was observed as perinuclear aggregates in the somata of the frontal cortex of SIV-infected macaques. Synaptosomes from SIV-infected animals were physiologically tested using a synaptic vesicle endocytosis assay and FM4-64 dye showing a significantly higher baseline depolarization levels in synaptosomes of SIV
    MeSH term(s) Animals ; Frontal Lobe/metabolism ; Frontal Lobe/virology ; Macaca mulatta ; Male ; Neurons/metabolism ; Neurons/virology ; Phosphorylation ; Protein Phosphatase 2/metabolism ; Simian Acquired Immunodeficiency Syndrome/metabolism ; Simian Acquired Immunodeficiency Syndrome/virology ; Simian Immunodeficiency Virus ; Synapses/metabolism ; Synapses/virology ; Synapsins/metabolism ; Synaptic Transmission/physiology ; Synaptosomes/metabolism ; Synaptosomes/virology ; Viral Load
    Chemical Substances Synapsins ; Protein Phosphatase 2 (EC 3.1.3.16)
    Language English
    Publishing date 2019-07-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.0178-19.2019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Predicting the spatial distribution of wintering golden eagles to inform full annual cycle conservation in western North America.

    Wallace, Zachary P / Bedrosian, Bryan E / Dunk, Jeffrey R / LaPlante, David W / Woodbridge, Brian / Smith, Brian W / Brown, Jessi L / Lickfett, Todd M / Gura, Katherine / Bittner, Dave / Crandall, Ross H / Domenech, Rob / Katzner, Todd E / Kritz, Kevin J / Lewis, Stephen B / Lockhart, Michael J / Miller, Tricia A / Quint, Katie / Shreading, Adam /
    Slater, Steve J / Stahlecker, Dale W

    PloS one

    2024  Volume 19, Issue 1, Page(s) e0297345

    Abstract: Wildlife conservation strategies focused on one season or population segment may fail to adequately protect populations, especially when a species' habitat preferences vary among seasons, age-classes, geographic regions, or other factors. Conservation of ...

    Abstract Wildlife conservation strategies focused on one season or population segment may fail to adequately protect populations, especially when a species' habitat preferences vary among seasons, age-classes, geographic regions, or other factors. Conservation of golden eagles (Aquila chrysaetos) is an example of such a complex scenario, in which the distribution, habitat use, and migratory strategies of this species of conservation concern vary by age-class, reproductive status, region, and season. Nonetheless, research aimed at mapping priority use areas to inform management of golden eagles in western North America has typically focused on territory-holding adults during the breeding period, largely to the exclusion of other seasons and life-history groups. To support population-wide conservation planning across the full annual cycle for golden eagles, we developed a distribution model for individuals in a season not typically evaluated-winter-and in an area of the interior western U.S. that is a high priority for conservation of the species. We used a large GPS-telemetry dataset and library of environmental variables to develop a machine-learning model to predict spatial variation in the relative intensity of use by golden eagles during winter in Wyoming, USA, and surrounding ecoregions. Based on a rigorous series of evaluations including cross-validation, withheld and independent data, our winter-season model accurately predicted spatial variation in intensity of use by multiple age- and life-history groups of eagles not associated with nesting territories (i.e., all age classes of long-distance migrants, and resident non-adults and adult "floaters", and movements of adult territory holders and their offspring outside their breeding territories). Important predictors in the model were wind and uplift (40.2% contribution), vegetation and landcover (27.9%), topography (14%), climate and weather (9.4%), and ecoregion (8.7%). Predicted areas of high-use winter habitat had relatively low spatial overlap with nesting habitat, suggesting a conservation strategy targeting high-use areas for one season would capture as much as half and as little as one quarter of high-use areas for the other season. The majority of predicted high-use habitat (top 10% quantile) occurred on private lands (55%); lands managed by states and the Bureau of Land Management (BLM) had a lower amount (33%), but higher concentration of high-use habitat than expected for their area (1.5-1.6x). These results will enable those involved in conservation and management of golden eagles in our study region to incorporate spatial prioritization of wintering habitat into their existing regulatory processes, land-use planning tasks, and conservation actions.
    MeSH term(s) Humans ; Animals ; Seasons ; Eagles ; Conservation of Natural Resources/methods ; North America ; Propylamines ; Sulfides
    Chemical Substances 1-(4-methylthiophenyl)-2-aminopropane ; Propylamines ; Sulfides
    Language English
    Publishing date 2024-01-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0297345
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  6. Article ; Online: Preclinical safety and biodistribution of CRISPR targeting SIV in non-human primates.

    Burdo, Tricia H / Chen, Chen / Kaminski, Rafal / Sariyer, Ilker K / Mancuso, Pietro / Donadoni, Martina / Smith, Mandy D / Sariyer, Rahsan / Caocci, Maurizio / Liao, Shuren / Liu, Hong / Huo, Wenwen / Zhao, Huaqing / Misamore, John / Lewis, Mark G / Simonyan, Vahan / Thompson, Elaine E / Xu, Ethan Y / Cradick, Thomas J /
    Gordon, Jennifer / Khalili, Kamel

    Gene therapy

    2023  

    Abstract: In this study, we demonstrate the safety and utility of CRISPR-Cas9 gene editing technology for in vivo editing of proviral DNA in ART-treated, virally controlled simian immunodeficiency virus (SIV) infected rhesus macaques, an established model for HIV ... ...

    Abstract In this study, we demonstrate the safety and utility of CRISPR-Cas9 gene editing technology for in vivo editing of proviral DNA in ART-treated, virally controlled simian immunodeficiency virus (SIV) infected rhesus macaques, an established model for HIV infection. EBT-001 is an AAV9-based vector delivering SaCas9 and dual guide RNAs designed to target multiple regions of the SIV genome: the viral LTRs, and the Gag gene. The results presented here demonstrate that a single IV inoculation of EBT-001 at each of 3 dose levels (1.4 × 10
    Language English
    Publishing date 2023-08-17
    Publishing country England
    Document type Journal Article
    ZDB-ID 1191036-7
    ISSN 1476-5462 ; 0969-7128
    ISSN (online) 1476-5462
    ISSN 0969-7128
    DOI 10.1038/s41434-023-00410-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Atrophy and Death of Nonpeptidergic and Peptidergic Nociceptive Neurons in SIV Infection.

    Robinson, Jake A / Guenthner, Guy / Warfield, Rebecca / Kublin, Jessica R / Smith, Mandy D / Shekarabi, Masoud / Miller, Andrew D / Burdo, Tricia H

    The American journal of pathology

    2020  Volume 190, Issue 7, Page(s) 1530–1544

    Abstract: ... populations were identified by neurofilament H-chain 200, I-B ...

    Abstract HIV-associated sensory neuropathy is a common neurologic comorbidity of HIV infection and prevails in the post-antiretroviral therapy (ART) era. HIV infection drives pathologic changes in the dorsal root ganglia (DRG) through inflammation, altered metabolism, and neuronal dysfunction. Herein, we characterized specific neuronal populations in an SIV-infected macaque model with or without ART. DRG neuronal populations were identified by neurofilament H-chain 200, I-B
    MeSH term(s) Animals ; Anti-Retroviral Agents/pharmacology ; Atrophy/pathology ; Ganglia, Spinal/drug effects ; Ganglia, Spinal/pathology ; Lectins/metabolism ; Macaca mulatta ; Male ; Nociceptors/drug effects ; Nociceptors/metabolism ; Nociceptors/pathology ; Polyneuropathies/pathology ; Polyneuropathies/virology ; Receptor, trkA/metabolism ; Simian Acquired Immunodeficiency Syndrome/pathology ; Simian Immunodeficiency Virus
    Chemical Substances Anti-Retroviral Agents ; Lectins ; Receptor, trkA (EC 2.7.10.1)
    Language English
    Publishing date 2020-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2943-9
    ISSN 1525-2191 ; 0002-9440
    ISSN (online) 1525-2191
    ISSN 0002-9440
    DOI 10.1016/j.ajpath.2020.03.004
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  8. Article ; Online: Racial discrimination and depressive symptoms mediated by conversations about race among students of color.

    DeLaney, Eryn N / Williams, Chelsea Derlan / Elias, Maria J / Walker, Chloe J / Smith, Tricia H / Adkins, Amy / Lozada, Fantasy T / Dick, Danielle M

    Journal of American college health : J of ACH

    2021  Volume 71, Issue 9, Page(s) 2835–2839

    Abstract: Racial discrimination is associated with adverse mental health outcomes among Students of Color. In order to address racial tensions, it is important to consider students' dialogues about race. The current study tested whether having positive and ... ...

    Abstract Racial discrimination is associated with adverse mental health outcomes among Students of Color. In order to address racial tensions, it is important to consider students' dialogues about race. The current study tested whether having positive and negative conversations about one's ethnic-racial group mediated the relation between racial discrimination at T1 and depressive symptoms 5 months later at T2 among 94 college Students of Color. Findings indicated that greater racial discrimination at T1 was associated with more frequent negative conversations about race at T2 (
    MeSH term(s) Humans ; Racism/psychology ; Depression/psychology ; Students/psychology ; Universities ; Mental Health
    Language English
    Publishing date 2021-11-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 604907-2
    ISSN 1940-3208 ; 0744-8481
    ISSN (online) 1940-3208
    ISSN 0744-8481
    DOI 10.1080/07448481.2021.1998071
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  9. Article ; Online: Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers in HIV: Mechanistic Substudy of the REPRIEVE Randomized Clinical Trial.

    Lu, Michael T / Ribaudo, Heather / Foldyna, Borek / Zanni, Markella V / Mayrhofer, Thomas / Karady, Julia / Taron, Jana / Fitch, Kathleen V / McCallum, Sara / Burdo, Tricia H / Paradis, Kayla / Hedgire, Sandeep S / Meyersohn, Nandini M / DeFilippi, Christopher / Malvestutto, Carlos D / Sturniolo, Audra / Diggs, Marissa / Siminski, Sue / Bloomfield, Gerald S /
    Alston-Smith, Beverly / Desvigne-Nickens, Patrice / Overton, Edgar T / Currier, Judith S / Aberg, Judith A / Fichtenbaum, Carl J / Hoffmann, Udo / Douglas, Pamela S / Grinspoon, Steven K

    JAMA cardiology

    2024  Volume 9, Issue 4, Page(s) 323–334

    Abstract: Importance: Cardiovascular disease (CVD) is increased in people with HIV (PWH) and is characterized by premature noncalcified coronary plaque. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), pitavastatin reduced major adverse ... ...

    Abstract Importance: Cardiovascular disease (CVD) is increased in people with HIV (PWH) and is characterized by premature noncalcified coronary plaque. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), pitavastatin reduced major adverse cardiovascular events (MACE) by 35% over a median of 5.1 years.
    Objective: To investigate the effects of pitavastatin on noncalcified coronary artery plaque by coronary computed tomography angiography (CTA) and on inflammatory biomarkers as potential mechanisms for MACE prevention.
    Design, setting, and participants: This double-blind, placebo-controlled randomized clinical trial enrolled participants from April 2015 to February 2018 at 31 US clinical research sites. PWH without known CVD who were taking antiretroviral therapy and had low to moderate 10-year CVD risk were included. Data were analyzed from April to November 2023.
    Intervention: Oral pitavastatin calcium, 4 mg per day.
    Main outcomes and measures: Coronary CTA and inflammatory biomarkers at baseline and 24 months. The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque.
    Results: Of 804 enrolled persons, 774 had at least 1 evaluable CTA. Plaque changes were assessed in 611 who completed both CT scans. Of 611 analyzed participants, 513 (84.0%) were male, the mean (SD) age was 51 (6) years, and the median (IQR) 10-year CVD risk was 4.5% (2.6-7.0). A total of 302 were included in the pitavastatin arm and 309 in the placebo arm. The mean noncalcified plaque volume decreased with pitavastatin compared with placebo (mean [SD] change, -1.7 [25.2] mm3 vs 2.6 [27.1] mm3; baseline adjusted difference, -4.3 mm3; 95% CI, -8.6 to -0.1; P = .04; 7% [95% CI, 1-12] greater reduction relative to placebo). A larger effect size was seen among the subgroup with plaque at baseline (-8.8 mm3 [95% CI, -17.9 to 0.4]). Progression of noncalcified plaque was 33% less likely with pitavastatin compared with placebo (relative risk, 0.67; 95% CI, 0.52-0.88; P = .003). Compared with placebo, the mean low-density lipoprotein cholesterol decreased with pitavastatin (mean change: pitavastatin, -28.5 mg/dL; 95% CI, -31.9 to -25.1; placebo, -0.8; 95% CI, -3.8 to 2.2). The pitavastatin arm had a reduction in both oxidized low-density lipoprotein (-29% [95% CI, -32 to -26] vs -13% [95% CI, -17 to -9]; P < .001) and lipoprotein-associated phospholipase A2 (-7% [95% CI, -11 to -4] vs 14% [95% CI, 10-18]; P < .001) compared with placebo at 24 months.
    Conclusions and relevance: In PWH at low to moderate CVD risk, 24 months of pitavastatin reduced noncalcified plaque volume and progression as well as markers of lipid oxidation and arterial inflammation. These changes may contribute to the observed MACE reduction in REPRIEVE.
    Trial registration: ClinicalTrials.gov Identifier: NCT02344290.
    MeSH term(s) Humans ; Male ; Middle Aged ; Female ; Coronary Artery Disease/diagnostic imaging ; Coronary Artery Disease/drug therapy ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Double-Blind Method ; Plaque, Atherosclerotic/diagnostic imaging ; Plaque, Atherosclerotic/drug therapy ; Inflammation/drug therapy ; Cardiovascular Diseases/drug therapy ; HIV Infections/complications ; HIV Infections/drug therapy ; Biomarkers ; Lipoproteins, LDL ; Quinolines
    Chemical Substances pitavastatin (M5681Q5F9P) ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Biomarkers ; Lipoproteins, LDL ; Quinolines
    Language English
    Publishing date 2024-02-21
    Publishing country United States
    Document type Journal Article ; Comment
    ISSN 2380-6591
    ISSN (online) 2380-6591
    DOI 10.1001/jamacardio.2023.5661
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  10. Article: A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma.

    Weiner, Amber K / Radaoui, Alexander B / Tsang, Matthew / Martinez, Daniel / Sidoli, Simone / Conkrite, Karina L / Delaidelli, Alberto / Modi, Apexa / Rokita, Jo Lynne / Patel, Khushbu / Lane, Maria V / Zhang, Bo / Zhong, Chuwei / Ennis, Brian / Miller, Daniel P / Brown, Miguel A / Rathi, Komal S / Raman, Pichai / Pogoriler, Jennifer /
    Bhatti, Tricia / Pawel, Bruce / Glisovic-Aplenc, Tina / Teicher, Beverly / Erickson, Stephen W / Earley, Eric J / Bosse, Kristopher R / Sorensen, Poul H / Krytska, Kateryna / Mosse, Yael P / Havenith, Karin E / Zammarchi, Francesca / van Berkel, Patrick H / Smith, Malcolm A / Garcia, Benjamin A / Maris, John M / Diskin, Sharon J

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor ... ...

    Abstract Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 60 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Moreover, DLK1 is highly expressed in several adult cancer types, including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG), hepatoblastoma, and small cell lung cancer (SCLC), suggesting potential clinical benefit beyond neuroblastoma. Taken together, our study demonstrates the utility of comprehensive cancer surfaceome characterization and credentials DLK1 as an immunotherapeutic target.
    Highlights: Plasma membrane enriched proteomics defines surfaceome of neuroblastomaMulti-omic data integration prioritizes DLK1 as a candidate immunotherapeutic target in neuroblastoma and other cancersDLK1 expression is driven by a super-enhancer
    Language English
    Publishing date 2024-01-07
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.06.570390
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