Showing papers by "University of Virginia published in 2023"

An intrinsic descriptor of perovskite cobaltites for catalytic peroxymonosulfate activation toward water remediation

Abstract: A series of strontium cobaltite perovskite oxides with various dopants (SrCo0.95M0.05O3-δ, M=Fe, Sc, Co, Zn, Gd) are designed for catalytic peroxymonosulfate (PMS) activation to degrade aqueous organic pollutants and the correlations between their crystalline structure and surface properties to catalytic activity were comprehensively investigated. SrCo0.95M0.05O3-δ displays three crystalline structures depending on the dopant metals and exhibits different catalytic activities. Among the structures and properties, Co-O bond length significantly affects the lattice oxygen diffusivity and Co2+/Co3+ redox capacity, governing the overall PMS activation, and is suggested as a descriptor for PMS activation. This study provides new insight to the reaction pathways and the structure-activity correlation for new design of effective perovskite oxides for PMS-based oxidation process toward wastewater treatment and other catalytic processes.

A Simple and Reproducible In Vivo Rabbit Phonation Model for Glottic Insufficiency

Abstract: The objective of this study is to describe an in vivo rabbit phonation model for glottic insufficiency that is simple and reproducible by means of unilateral transcricothyroid laryngeal muscle stimulation and high-speed video recordings of evoked phonation.Nonrandomized controlled animal trial.Academic medical center.A single operation including evoked phonation with bilateral and unilateral transcricothyroid laryngeal muscle stimulation conditions was modeled using 6 New Zealand white rabbits. The effect of stimulation method on glottic cycle, pitch, and loudness was compared. Endoscopic recordings using 5000 frames-per-second image capture technology and audiologic recordings were obtained for all phonation conditions. Primary outcome measures included means of maximum glottal area (MGA)/length pixel ratio, right and left amplitude/length pixel ratios, calculated cycle frequency, auditory recorded frequency, and maximum auditory intensity. Measurements were obtained via pixel counts using ImageJ.Mean MGA/length was significantly greater with unilateral, 20.30, vs bilateral, 9.62, stimulation (P = .043). Mean frequency of 479.92 Hz vs 683.46 Hz (P = .027) and mean maximum intensity of 76.3 dB vs 83.5 dB (P = .013) were significantly increased from unilateral to bilateral stimulation. There was no significant difference in mean right amplitude/length between unilateral and bilateral.The described model demonstrates a simple and reproducible means of producing glottic insufficiency due to unilateral vocal fold bowing and represents a pathway for better understanding the biomechanics and pathophysiology of glottic insufficiency due to superior laryngeal nerve injury and vocal fold immobility and offers the potential to compare treatment modalities through in vivo study.

Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial

Abstract: To explore whether patients with BRCA1/2-mutated or homologous recombination deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial.Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. Programmed death-ligand 1 (PD-L1) status of tumor-infiltrating immune cells (IC) was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥ 16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan-Meier estimates.Among biomarker-evaluable samples, 22% (234/1,050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1,024) had TMB ≥10 mut/Mb, and 0.3% (3/1,022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2-non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on ICs) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors.Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors. See related commentary by Al-Rawi et al., p. 1645.

Tertiary lymphoid structures in desmoplastic melanoma have increased lymphocyte density, lymphocyte proliferation, and immune cross talk with tumor when compared to non-desmoplastic melanomas

Abstract: Tertiary lymphoid structures (TLS) are ectopic lymphoid structures that can arise in human cancers and are associated with improved overall survival (OS) and response to immune checkpoint blockade (ICB) in several cancers, including non-desmoplastic metastatic melanoma (NDMM). Desmoplastic melanoma (DM) has one of the highest response rates to ICB, and we previously identified that primary DM (PDM) contains TLS. Despite the association of TLS with survival and ICB response, it is unknown whether TLS or associated markers of immune activity can differ between PDM and NDMM. We hypothesized that PDM would contain higher frequencies of TLS than NDMM, that T and B-cell densities and proliferation would be greater in TLS of PDM than TLS of NDMM, and that proliferation rates of T and B-cells in PDM TLS would be concordant with those of intratumoral lymphocytes. We found that four features of TLS in PDM distinguish them from TLS in NDMM. TLS were peritumoral in NDMM but intratumoral in PDM. CD8+ T-cell and CD20+ B-cell densities and proliferative fractions were higher in PDM TLS than NDMM TLS. Additionally, the proliferative fractions of T- and B-cells were concordant between the TLS and tumor site in PDM and discordant in NDMM. Collectively, these data suggest that TLS and associated immune markers can differ across melanoma subsets and suggest that PDM TLS may be more immunologically active and have enhanced immune cell trafficking between tumor and TLS compared to NDMM.

A genetically encoded far-red fluorescent indicator for imaging synaptically released Zn ²⁺

Abstract: Synaptic zinc ion (Zn2+) has emerged as a key neuromodulator in the brain. However, the lack of research tools for directly tracking synaptic Zn2+ in the brain of awake animals hinders our rigorous understanding of the physiological and pathological roles of synaptic Zn2+. In this study, we developed a genetically encoded far-red fluorescent indicator for monitoring synaptic Zn2+ dynamics in the nervous system. Our engineered far-red fluorescent indicator for synaptic Zn2+ (FRISZ) displayed a substantial Zn2+-specific turn-on response and low-micromolar affinity. We genetically anchored FRISZ to the mammalian extracellular membrane via a transmembrane (TM) ⍺ helix and characterized the resultant FRISZ-TM construct at the mammalian cell surface. We used FRISZ-TM to image synaptic Zn2+ in the auditory cortex in acute brain slices and awake mice in response to electric and sound stimuli, respectively. Thus, this study establishes a technology for studying the roles of synaptic Zn2+ in the nervous system.

Perspectives on Access to Novel Therapeutics Through Clinical Trials Among Adolescents and Young Adults with Advanced Cancer: Implications for Patient-Centered Clinical Trials

Abstract: Purpose: Adolescents and young adults (AYA) with advanced cancer have unequal access to and enrollment in clinical trials. Many AYA use online platforms to share their treatment experiences. The purpose of this analysis was to explore how AYA discuss clinical trials and their access to novel therapeutics through their blogs. Methods: We studied illness blogs from 22 AYA (ages 16-38 years old) with advanced cancer who specifically discussed experiences enrolling in a clinical trial. Nearly 500 excerpts were abstracted from their blogs, and we used qualitative descriptive methodology and thematic analysis to explore their longitudinal perspectives. Results: We describe three themes: (1) "Blinded", which represents the uncertainty in treatment pathway and underrepresentation of AYA in clinical trials, (2) "Totally healthy except for the damn cancer", which represents the numerous challenges associated with meeting eligibility criteria and lack of available clinical trials, and (3) "Go ahead and send me the bill!", which represents the precarious financial challenges associated with participating with clinical trials (both direct costs and indirect costs associated with travel, time away from work) as well as the costs of novel therapeutics. Conclusions: By studying AYA online narratives, we can outline several gaps in accessing clinical trials and generate future research priorities. AYA with advanced cancer are known to have aggressive trajectories, and there are opportunities to integrate patient-reported outcomes and supportive care frameworks embedded within clinical trial study design.

Reproductive Coercion Among Women With Disabilities

Abstract: Background/Aims Reproductive coercion (RC) is a widespread yet understudied type of intimate partner violence that is associated with numerous negative outcomes. Women with disabilities may be at an increased risk of RC; however, little research has been conducted among this population. Using population-based data, we sought to examine the prevalence of RC in postpartum women with disabilities. Methods This is a secondary analysis of a cross-sectional survey, the Pregnancy Risk Assessment Monitoring System, a nationally representative survey conducted by the Centers for Disease Control and Prevention in partnership with participating states. These analyses include 3,117 respondents who had information on both disability status and experiences of RC. Results Approximately 1.9% of respondents reported experiencing RC (95% CI [1.3, 2.4]). When stratified by disability status, approximately 1.7% of respondents without a disability reported RC whereas 6.2% of respondents with at least one disability reported RC (p < 0.001). In univariable logistic models, disability, age, education, relationship status, income, and race were all significantly associated with RC. Conclusions Our findings highlight the need for healthcare providers working with women with disabilities to screen for RC and potentially uncover intimate partner violence and prevent its negative health consequences. All states participating in Pregnancy Risk Assessment Monitoring System data collection are urged to incorporate measures of RC and disability status to better address this significant issue.

Phagocytosis via complement receptor 3 enables microbes to evade killing by neutrophils

Abstract: Abstract CR3 (CD11b/CD18; αmβ2 integrin) is a conserved phagocytic receptor. The active conformation of CR3 binds the iC3b fragment of complement C3 as well as many host and microbial ligands, leading to actin-dependent phagocytosis. There are conflicting reports about how CR3 engagement affects the fate of phagocytosed substrates. Using imaging flow cytometry, we confirmed that binding and internalization of iC3b-opsonized polystyrene beads by primary human neutrophils was CR3-dependent. iC3b-opsonized beads did not stimulate neutrophil reactive oxygen species, and most beads were found in primary granule-negative phagosomes. Similarly, Neisseria gonorrhoeae that does not express phase-variable Opa proteins suppresses neutrophil reactive oxygen species and delays phagolysosome formation. Here, binding and internalization of Opa-deleted (Δopa) N. gonorrhoeae by adherent human neutrophils was inhibited using blocking antibodies against CR3 and by adding neutrophil inhibitory factor, which targets the CD11b I-domain. No detectable C3 was deposited on N. gonorrhoeae in the presence of neutrophils alone. Conversely, overexpressing CD11b in HL-60 promyelocytes enhanced Δopa N. gonorrhoeae phagocytosis, which required the CD11b I-domain. Phagocytosis of N. gonorrhoeae was also inhibited in mouse neutrophils that were CD11b-deficient or treated with anti-CD11b. Phorbol ester treatment upregulated surface CR3 on neutrophils in suspension, enabling CR3-dependent phagocytosis of Δopa N. gonorrhoeae. Neutrophils exposed to Δopa N. gonorrhoeae had limited phosphorylation of Erk1/2, p38, and JNK. Neutrophil phagocytosis of unopsonized Mycobacterium smegmatis, which also resides in immature phagosomes, was CR3-dependent and did not elicit reactive oxygen species. We suggest that CR3-mediated phagocytosis is a silent mode of entry into neutrophils, which is appropriated by diverse pathogens to subvert phagocytic killing.

Intratumoral IFN-γ or topical TLR7 agonist promotes infiltration of melanoma metastases by T lymphocytes expanded in the blood after cancer vaccine

Abstract: Background Immune-mediated melanoma regression relies on melanoma-reactive T cells infiltrating tumor. Cancer vaccines increase circulating melanoma-reactive T cells, but little is known about vaccine-induced circulating lymphocytes (viCLs) homing to tumor or whether interventions are needed to enhance infiltration. We hypothesized that viCLs infiltrate melanoma metastases, and intratumoral interferon (IFN)-γ or Toll-like receptor 7 (TLR7) agonism enhances infiltration. Methods Patients on two clinical trials (Mel51 ( NCT00977145 ), Mel53 ( NCT01264731 )) received vaccines containing 12 class I major histocompatibility complex-restricted melanoma peptides (12MP). In Mel51, tumor was injected with IFN-γ on day 22, and biopsied on days 1, 22, and 24. In Mel53, dermal metastases were treated with topical imiquimod, a TLR7 agonist, for 12 weeks, and biopsied on days 1, 22, and 43. For patients with circulating T-cell responses to 12MP by IFN-γ ELISpot assays, DNA was extracted from peripheral blood mononuclear cells (PBMCs) pre-vaccination and at peak T-cell response, and from tumor biopsies, which underwent T-cell receptor sequencing. This enabled identification of clonotypes induced in PBMCs post-vaccination (viCLs) and present in tumor post-vaccination, but not pre-vaccination. Results Six patients with T-cell responses post-vaccination (Mel51 n = 4, Mel53 n = 2) were evaluated for viCLs and vaccine-induced tumor infiltrating lymphocytes (viTILs). All six patients had viCLs, five of whom were evaluable for viTILs in tumor post-vaccination alone. Mel51 patients had viTILs identified in day 22 tumors, post-vaccination and before IFN-γ (median = 2, range = 0–24). This increased in day 24 tumors after IFN-γ (median = 30, range = 4–74). Mel53 patients had viTILs identified in day 22 tumors, post-vaccination plus imiquimod (median = 33, range = 2–64). Three of five evaluable patients across both trials had viTILs with vaccination alone. All five had enhancement of viTILs with tumor-directed therapy. viTILs represented 0.0–2.9% of total T cells after vaccination alone, which increased to 0.6–8.7% after tumor-directed therapy. Conclusion Cancer vaccines induce expansion of new viCLs, which infiltrate melanoma metastases in some patients. Our findings identify opportunities to combine vaccines with tumor-directed therapies to enhance T-cell infiltration and T cell-mediated tumor control. These combinations hold promise in improving the therapeutic efficacy of antigen-specific therapies for solid malignancies.

Machine learning nonequilibrium electron forces for spin dynamics of itinerant magnets

Abstract: Abstract We present a generalized potential theory for conservative as well as nonconservative forces for the Landau-Lifshitz magnetization dynamics. Importantly, this formulation makes possible an elegant generalization of the Behler-Parrinello machine learning (ML) approach, which is a cornerstone of ML-based quantum molecular dynamics methods, to the modeling of force fields in adiabatic spin dynamics of out-of-equilibrium itinerant magnetic systems. We demonstrate our approach by developing a deep-learning neural network that successfully learns the electron-mediated exchange fields in a driven s-d model computed from the nonequilibrium Green’s function method. We show that dynamical simulations with forces predicted from the neural network accurately reproduce the voltage-driven domain-wall propagation. Our work also lays the foundation for ML modeling of spin transfer torques and opens a avenue for ML-based multi-scale modeling of nonequilibrium dynamical phenomena in itinerant magnets and spintronics.

Applicability of Extreme Vertices Design in the Compositional Optimization of 3D-Printed Lightweight High-Entropy-Alloy/B4C/ZrO2/Titanium Trihybrid Aero-Composite

Abstract: Recent studies have shown the benefits of utilizing ceramic particles as reinforcement in metal alloys; nevertheless, certain drawbacks, including loss of ductility, embrittlement, and decreases in toughness, have been noted. For the objective of obtaining balanced performance, experts have suggested the addition of metal particles as supplement to the ceramic reinforcement. Consequently, high-performance metal hybrid composites have been developed. However, achieving the optimal mix for the reinforcement combination with regards to the optimal performance of developed composite remains a challenge. This research aimed to determine the optimal mixture of Al50Cu10Sn5Mg20Zn10Ti5 lightweight high-entropy alloy (LHEA), B4C, and ZrO2 for the fabrication of trihybrid titanium composites via direct laser deposition. A mixture design was involved in the experimental design, and experimental data were modeled and optimized to achieve the optimal performance of the trihybrid composite. The ANOVA, response surface plots, and ternary maps analyses of the experimental results revealed that various combinations of reinforcement particles displayed a variety of response trends. Moreover, the analysis showed that these reinforcements significantly contributed to the magnitudes and trends of the responses. The generated models were competent for predicting response, and the best formulation consisted of 8.4% LHEA, 1.2% B4C, and 2.4% ZrO2.

Use of placebo in clinical trials in COVID-19 pandemic times: considerations on pros, cons, challenges and limitations

Abstract: The ongoing coronavirus disease 2019 (COVID-19) pandemic has placed tremendous strain on health systems throughout the world. This has led to many clinical trials being launched in order to try to find ways to combat the disease. The unprecedented nature of the pandemic has been reflected in the methods used in some of these trials. Placebo-controlled randomized trials are considered the gold-standard, however, there are inherent challenges in the use of placebo, especially during COVID-19. We herein review the pros, cons, challenges and limitations of using placebo in clinical trials investigating treatments for COVID-19. We also discuss the importance of viewing research critically, examining the potential impact of placebo use or lack thereof, on blinding and possible biases. This becomes important as we assess the responses to the pandemic in preparation for a future pandemic. Although placebo-controlled clinical trials are the gold standard for clinical research, they may not be practically or ethically feasible during a pandemic. Choices accomplished to design many COVID-19 trials might reflect the unprecedently trying environment in which they were made. However, critical evaluation of the methodology and practice of scientific research remains a crucial part of the scientific process. Even when conducted as randomized double-blind studies, residual biases may exist and interfere with the study conduct and interpretation of the data. A critical review of all data remains essential to thoroughly assess the impact of a research study.

Angloglobalism, multilingualism and world literature

Abstract: This essay explores the rise of global anglophone as a methodological rubric, and the place of English in global literary studies. My exposition pivots around a set of interwoven claims. While contemporary globalization has led to increasing linguistic homogenization, the rise of global anglophone does not herald the end of postcolonialism nor is it a force bent on erasing the cultural and linguistic diversity of literatures of the world. Rather, its valence can be generatively explored in the context of recent debates about the provenance of comparative and world literatures, and the emergence of multilingual transregional literary enclaves that are smaller than the globe and larger than a nation. Wariness about the moral economy of the angloglobalism can often be in tension with contemporary processes of anglophone transculturation. Further, the rise of global anglophone is inseparable from current debates in translation studies and the emergence of English as a global vernacular and a target language. Lastly, the global dominance of English appears less threatening when visualized through a comparative historical lens that illuminates the role of other world languages. As scholarship on premodern and early modern cultures indicates, linguistic cosmopolitanism and vernacular expressivity have not typically existed as antinomian forces in literary history.

Characterizing Average Seasonal, Synoptic, and Finer Variability in Orbiting Carbon Observatory‐2 XCO ₂ Across North America and Adjacent Ocean Basins

Abstract: Variations in atmosphere total column-mean CO2 (XCO2) collected by the National Aeronautics and Space Administration's Orbiting Carbon Observatory-2 satellite can be used to constrain surface carbon fluxes if the influence of atmospheric transport and observation errors on the data is known and accounted for. Due to sparse validation data, the portions of fine-scale variability in XCO2 driven by fluxes, transport, or retrieval errors remain uncertain, particularly over the ocean. To better understand these drivers, we characterize variability in OCO-2 Level 2 version 10 XCO2 from the seasonal scale, synoptic-scale (order of days, thousands of kilometers), and mesoscale (within-day, hundreds of kilometers) for 10 biomes over North America and adjacent ocean basins. Seasonal and synoptic variations in XCO2 reflect real geophysical drivers (transport and fluxes), following large-scale atmospheric circulation and the north-south distribution of biosphere carbon uptake. In contrast, geostatistical analysis of mesoscale and finer variability shows that real signals are obscured by systematic biases across the domain. Spatial correlations in along-track XCO2 are much shorter and spatially coherent variability is much larger in magnitude than can be attributed to fluxes or transport. We characterize random and coherent along-track XCO2 variability in addition to quantifying uncertainty in XCO2 aggregates across typical lengths used in inverse modeling. Even over the ocean, correlated errors decrease the independence and increase uncertainty in XCO2. We discuss the utility of computing geostatistical parameters and demonstrate their importance for XCO2 science applications spanning from data reprocessing and algorithm development to error estimation and carbon flux inference.

Wolff–Parkinson–White Syndrome

Abstract: The Wolff–Parkinson–White syndrome (WPW) is a ventricular preexcitation syndrome involving the electrocardiographic combination of bundle branch block and shortened PR interval; a number of these patients, who are healthy with otherwise normal hearts, experience recurrent episodes of supraventricular tachycardias. To be diagnosed with the WPW syndrome, the patient must demonstrate the electrocardiographic findings in sinus rhythm as well as symptomatic tachydysrhythmias, including paroxysmal supraventricular tachycardia, atrial fibrillation, atrial flutter, and ventricular fibrillation (rare). Atrial fibrillation is also seen in the WPW patient; it is the second most frequent rhythm disturbance encountered in these patients. The chapter also provides a simplified approach to rhythm differentiation in the WPW syndrome. Obviously, ventricular fibrillation is life threatening – whether it is related to WPW or not.

Somānanda’s <i>Śivadṛṣṭi</i> as an Argument against Dharmakīrti

Abstract: Abstract It is well known that the philosophy of the Buddhist epistemologist Dharmakīrti pervasively influenced the Kashmirian Pratyabhijñā philosopher Utpaladeva (fl. ca. 925–975 CE) and, through him, his grand-disciple Abhinavagupta (fl. ca. 975–1025 CE). This chapter will demonstrate the centrality of the same in the thinking of Utpaladeva’s teacher, Somānanda (fl. ca. 900–950 CE), the founding author of the Pratyabhijñā. Somānanda’s magnum opus, the Śivadṛṣṭi, though it is an eclectic and ranging work that engages a great variety of esoteric religious traditions and orthodox Hindu and Buddhist philosophical schools, takes as a central task the parrying of Dharmakīrti’s antipersonalist philosophy, this by engaging many of its elements in order to articulate a hyperpersonalist and realist, if simultaneously monist, Śaiva ontology. This chapter traces these Buddhist influences in Somānanda’s text and establishes thereby a basis for weighing its legacies in the writings of those who follow him in the guru-śiṣya lineage of the Kashmiri Pratyabhijñā.

Cells of the Renin Lineage Promote Kidney Regeneration <scp>Post‐Release</scp> of Ureteral Obstruction in Neonatal Mice.

Abstract: Aim Ureteral obstruction leads to significant changes in kidney renin expression. It is unclear whether those changes are responsible for the progression of kidney damage, repair, or regeneration. In the current study, we aimed to elucidate the contribution of renin-producing cells (RPCs) and the cells of renin lineage (CoRL) towards kidney damage and regeneration using a model of partial and reversible unilateral ureteral obstruction (pUUO) in neonatal mice. Methods Renin cells are progenitors for other renal cell types collectively called CoRL. We labeled the CoRL with Green Fluorescent Protein (GFP) using genetic approaches. We performed lineage tracing to analyze the changes in the distribution of CoRL during and after the release of obstruction. We also ablated the RPCs and CoRL by cell-specific expression of Diptheria Toxin Sub-unit A (DTA). Finally, we evaluated the kidney damage and regeneration during and after the release of obstruction in the absence of CoRL. Results: In the obstructed kidneys, there was a 163% increase in the renin-positive area and a remarkable increase in the distribution of GFP+ CoRL. Relief of obstruction abrogated these changes. In addition, DTA-expressing animals did not respond to pUUO with increased RPCs and CoRL. Moreover, reduction in CoRL significantly compromised the kidney's ability to recover from the damage after the release of obstruction. Conclusions CoRL play a role in the regeneration of the kidneys post-relief of obstruction. This article is protected by copyright. All rights reserved.

Spectroscopy characterization of quantum modes in an on-chip squeezed microcomb

Abstract: We characterized the spectrum of 40 quantum modes in an on-chip squeezed microcomb. A theoretical model is developed to explain how cavity dispersion affects the squeezing and the frequency equidistance of these quantum modes.

Data from Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells

Abstract: <div><p>The ADP-ribosyltransferase PARP7 modulates protein function by conjugating ADP-ribose to the side chains of acceptor amino acids. PARP7 has been shown to affect gene expression in prostate cancer cells and certain other cell types by mechanisms that include transcription factor ADP-ribosylation. Here, we use a recently developed catalytic inhibitor to PARP7, RBN2397, to study the effects of PARP7 inhibition in androgen receptor (AR)-positive and AR-negative prostate cancer cells. We find that RBN2397 has nanomolar potency for inhibiting androgen-induced ADP-ribosylation of the AR. RBN2397 inhibits the growth of prostate cancer cells in culture when cells are treated with ligands that activate the AR, or the aryl hydrocarbon receptor, and induce PARP7 expression. We show that the growth-inhibitory effects of RBN2397 are distinct from its enhancement of IFN signaling recently shown to promote tumor immunogenicity. RBN2397 treatment also induces trapping of PARP7 in a detergent-resistant fraction within the nucleus, which is reminiscent of how inhibitors such as talazoparib affect PARP1 compartmentalization. Because PARP7 is expressed in AR-negative metastatic tumors and RBN2397 can affect cancer cells through multiple mechanisms, PARP7 may be an actionable target in advanced prostate cancer.</p>Significance:<p>RBN2397 is a potent and selective inhibitor of PARP7 that reduces the growth of prostate cancer cells, including a model for treatment-emergent neuroendocrine prostate cancer. RBN2397 induces PARP7 trapping on chromatin, suggesting its mechanism of action might be similar to clinically used PARP1 inhibitors.</p></div>