Medicine and Health Sciences Commons^™

Synergistic Effects Of Diabetic Neuropathy And Kidney Function Decline On Second Metatarsal Skeletal Health And Foot Function: A Pilot Study, Victor A Cheuy, Saghi Sadoughi, Hasung Moon, Jalen Ellis, Rodney Gross, David R Sinacore, Mary K Hastings, Richard B Souza, Galateia J Kazakia

2020-Current year OA Pubs

A discouraging increase in diabetes-related nontraumatic lower-extremity amputations (NLEA) has occurred over the last decade. Individuals with diabetic neuropathy (DMPN) and CKD are at the highest risk for NLEA. Despite the critical implications, little is known about the factors that initiate the cascade of events leading to NLEA, limiting early and effective interventions. We aimed to develop and implement a technique for quantifying metatarsal bone density and microstructure using HR-pQCT. Twelve participants were enrolled:

Expanding The Omop Common Data Model To Support Extracorporeal Life Support Research, Clemens Rieder, Ahmed Said, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Despite the increased availability of electronic health records, open-source standardized data collection to facilitate high-resolution data during extracorporeal life support (ECLS) is lacking. This project aimed to assess the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) for interoperability to store data sufficiently generated in the context of ECLS and to develop a custom data model expansion in case the OMOP CDM proved insufficient.

DESIGN AND SETTING: The OMOP CDM was analyzed qualitatively by expert consensus for its capability to capture data relative to ECLS as well as the presence of fitting ECLS-related concepts. Database entries necessary to …

Frame-Wise Multi-Echo Distortion Correction For Superior Functional Mri, Andrew N Van, David F Montez, Timothy O Laumann, Philip N Cho, Vahdeta Suljic, Noah J Baden, Nadeshka Ramirez-Perez, Kristen M Scheidter, Julia S Monk, Forrest I Whiting, Babatunde Adeyemo, Roselyne J Chauvin, Samuel R Krimmel, Athanasia Metoki, Aishwarya Rajesh, Jarod L Roland, Anxu Wang, Aristeidis Sotiras, Joshua S Shimony, Benjamin P Kay, Scott A Marek, Evan M Gordon, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

Functional MRI (fMRI) data are severely distorted by magnetic field (B0) inhomogeneities, which currently must be corrected using separately acquired field map data. However, changes in the head position of a participant across fMRI frames cause changes in the B0 field, preventing accurate correction of geometric distortions. Movement during field map acquisitions corrupts field maps, preventing distortion correction altogether. In this study, we use multi-echo (ME) fMRI data to dynamically sample and correct for magnetic field image distortions caused by head motion. Our distortion correction pipeline, MEDIC (Multi-Echo DIstortion Correction), leverages magnetic field inhomogeneity information found in the difference between …

Inflammaging In Aged Tissues Drives Remodeling Of The Cd8+ T Cell Compartment, Irina Shchukina, Carlos J Rodriguez-Hernandez, Heather S Ruiz, Maksim Kleverov, Rachel L Mintz, Katsutaka Mineura, Subhadra C Gunawardana, Sunnie Hsiung, Bishan Bhattarai, Veronika Vachova, Jan Kossl, Denis A Mogilenko, Rachael L Field, Tran H Nguyen, Quazim A Alayo, Christopher G Huckstep, Barbora Vander Wielen, Jonathan R Brestoff, Sheila A Stewart, David W Piston, Takeshi Egawa, Daniel Kreisel, Gwendalyn J Randolph, Maxim N Artyomov

2020-Current year OA Pubs

Aging strongly impacts CD8

Patterns Of Care And Clinical Outcomes In Systemic Peripheral T-Cell Lymphoma: The Leo-Mer Prospective Cohort Study, Jia Ruan, Neha Mehta-Shah, Brad Kahl, Et Al.

2020-Current year OA Pubs

Few prospective benchmark studies exist to characterize the evolving contemporary real-world practice for peripheral T-cell lymphoma (PTCL). We report the patterns of first-line care and outcomes for 720 patients with systemic PTCL enrolled in 2 related prospective cohort studies, Lymphoma Epidemiology of Outcomes (LEO) from 2015 to 2020 and Molecular Epidemiology Resource (MER) from 2002 to 2015, both followed to 2024. The primary end points were event-free survival (EFS) and overall survival (OS) using Kaplan-Meier estimator and Cox regression model. Secondary end points included correlations of clinical and treatment factors with survival. The most common induction regimens were CHOP (cyclophosphamide, …

Regulation Of Pfh1 Helicase Activity By Nucleic Acid Interactions And Mitochondrial Ssb, María Ortiz-Rodríguez, Saurabh P Singh, Francisco J Cao-García, Roberto Galletto, Borja Ibarra

2020-Current year OA Pubs

Pif1-family helicases are essential for proper nuclear and mitochondrial genome maintenance, yet the regulation of their activities remains incompletely understood. Here, we use single-molecule manipulation and visualization techniques to dissect the real-time mechanochemical behavior of Pfh1, the sole Pif1-family helicase in

Efficacy And Safety Of Avapritinib In Advanced Systemic Mastocytosis: 4-Year Follow-Up Of The Pathfinder Study, Jason Gotlib, Stephen T Oh, Et Al.

2020-Current year OA Pubs

Advanced systemic mastocytosis (AdvSM), a clonal hematologic neoplasm driven predominantly by D816V-mutant KIT, is often characterized by organ damage. Associated hematologic neoplasms (AHNs; usually myeloid) are often present, leading to poor survival. We report on the oral, highly selective, potent KIT D816V inhibitor avapritinib (200 mg once daily, starting dose) with >4 years follow-up from the fully enrolled PATHFINDER study. End points included overall response rate (ORR; primary), duration of response (DOR), progression-free survival (PFS), overall survival (OS), changes in objective biomarkers of disease, and safety (all secondary). Of 107 patients with AdvSM (including 71 [66%] with SM-AHN; overall population …

Isg15 Negatively Regulates Ripk3-Mediated Cell Death And Viral Pathogenesis, Yi-Chieh Perng, Jessica M C Warsaw, Sachendra S Bais, Bradley E Hiller, Marissa C Locke, David J Morales-Heil, Chaoqun Li, Alissa R Young, Kristen J Monte, Robert E Schmidt, Douglas R Green, Yi-Nan Gong, Deborah J Lenschow

2020-Current year OA Pubs

Necroptosis, a form of programmed, inflammatory necrosis, plays an important role in viral-host defense and inflammation. The receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway mediates necroptosis. Yet, the mechanisms that control necroptosis to limit immunopathology are poorly understood. Here, we report that interferon-stimulated gene 15 (ISG15) negatively regulates RIPK3-mediated cell death, including necroptosis, and limits immunopathology during chikungunya virus (CHIKV) infection. ISG15-deficient mice infected with CHIKV display increased levels of necroptosis, resulting in elevated proinflammatory cytokine and chemokine production, leading to increased lethality. This dysregulated host response is fully prevented when MLKL or RIPK3 is ablated …

Generalizability Of An Ai-Based Mammogram Risk Score (Mrs) For Breast Cancer Among Diverse Populations Of Women, Shu Jiang, Debbie L Bennett, Peter Kraft, Graham A Colditz

2020-Current year OA Pubs

Conventional prediction models incorporating genetic and clinical factors including breast density underperform in non-European populations. We investigated an artificial intelligence-derived mammogram risk score (MRS), a summary of texture features that captures intrinsic breast-tissue characteristics-the substrate for cancer development. This study leveraged data from two North American screening cohorts totaling >226,000 women, including non-Hispanic white, non-Hispanic Black, East Asian, South Asian, and Indigenous women. MRS distributions showed nonsignificant shifts (and similar SDs) between cohorts and across race and ethnic subgroups. MRS increased with age and was significantly associated with breast cancer risk, with hazard ratios per SD ranging from 2.24 [95% …

Dual Orexin Receptor Antagonism With Lemborexant Enhances Microglial Clearance Of Β-Amyloid In Mice, Ashish Sharma, Emiko Segawa, Xiaoying Chen, Sohui Park, Shoutang Wang, Riley E Irmen, Nicholas J Constantino, Chanung Wang, Michael F Kanan, Marco Colonna, Shannon L Macauley, Jocelyn Y Cheng, Ken Hatanaka, Margaret Moline, Erik S Musiek

2020-Current year OA Pubs

BACKGROUND: Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer's disease (AD). The orexin/hypocretin system regulates sleep-wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.

METHODS: PSAPP mice received lemborexant (10 or 30 mg/kg/day), doxepin (35 mg/kg/day), or vehicle for 6 weeks beginning prior to plaque onset or 4 weeks after established pathology. Sleep was assessed …

Longitudinal Changes In Cognition And Brain Imaging In Persons With Human Immunodeficiency Virus, James Kennedy, Sarah A Cooley, June Roman Fox, Kalen J Petersen, Elizabeth Westerhaus, Pat Reid, Linet Lopez, Beau M Ances

2020-Current year OA Pubs

BACKGROUND: As persons with human immunodeficiency virus (PWH) live longer, interactions between human immunodeficiency virus (HIV), aging, and structural brain integrity become increasingly vital for understanding cognitive disorders. This study analyzed the effects of aging, HIV serostatus, and viral load on cognition and brain volumes in a large cohort of persons without HIV (PWOH), PWH with undetectable virus (PWHU) (HIV RNA ≤50 copies/mL), and PWH with detectable virus (PHWD) (HIV RNA >50 copies/mL). Cross-sectional and longitudinal data were included.

METHODS: Cognitive composites (NPZ4) and brain volumes were obtained from 259 PWOH, 264 PWHU, and 84 PWHD with a total of …

Subclinical Neuropsychiatric Trait Variation In Parents Of Children With Autism Spectrum Disorder: A Cohort Study, Lindsay J Mullin, Carolyn Lasch, Natasha Marrus, Et Al.

2020-Current year OA Pubs

BACKGROUND: Many neuropsychiatric conditions share overlapping features underpinned by shared genetics. In this study, we examined the co-aggregation of sub-threshold variation in neuropsychiatric phenotypes in biological parents of autistic children to provide insights into the intergenerational transmission of genetic liability for autism.

METHODS: Autistic, neuropsychiatric (i.e., anxiety, depression, ADHD), and cognitive traits were characterized in biological parents of children enrolled in a longitudinal developmental study: 189 families of autistic children and 100 families with no autistic children were included. Families were further characterized as having only one (simplex) or more than one (multiplex) autistic child. Maternal and paternal traits were …

Quantification Of Sarm1 Nadase Activity In Human Peripheral Blood Mononuclear Cells, Lila F Dabill, Ivana R Shen, Jennifer M Brazill, Alicia Neiner, Yo Sasaki, Erica L Scheller

2020-Current year OA Pubs

SARM1 (sterile α and TIR motif-containing protein-1) is an NADase enzyme that serves as the central executioner of Wallerian axon degeneration. Given this, SARM1 is of high interest as a candidate therapeutic target, and SARM1 inhibitors are currently in clinical trials for treatment of neurodegeneration. Beyond neuroscience, emerging studies reveal that SARM1 may also drive aspects of bone fragility, liver pathology, adipose expansion, and insulin resistance in metabolic disease. However, we lack methods to quantify SARM1 activation in humans to better define patients at high risk of SARM1-mediated tissue damage. Unlike neurons, peripheral blood mononuclear cells (PBMCs) represent an easily …

Making Process Evaluations More Explanatory - Key Opportunities To Advance Implementation Research, Michel Wensing, Elvin H Geng

2020-Current year OA Pubs

Process evaluation of implementation strategies is increasingly common, but a review by Bracci et al. showed that room for improvement exists. In this contribution, we complement their recommendations by ideas on the design of process evaluations. Process evaluations are meant to provide explanations for why implementation strategies were effective, or not effective. Therefore, they are best guided by theory or frameworks, but the frequent focus on intervention acceptability reflects a lack of imagination on moderators and mediators that influence outcomes. Intervention fidelity is relevant in all process evaluations. Meaningful synthesis of process evaluation studies requires a homogeneous outcome, such as …

Simultaneous Multielectrode Recordings Along The Human Scala Tympani: Evidence For Level-Dependent Place Coding, Amit Walia, Matthew A Shew, Shannon M Lefler, Amanda J Ortmann, Patrick Ioerger, Jordan Varghese, Jacques A Herzog, Craig A Buchman

2020-Current year OA Pubs

The cochlea systematically encodes sound frequency and intensity via a precisely organized tonotopic map, in which traveling waves peak at specific cochlear locations. A fundamental but incompletely understood aspect of auditory coding involves how stimulus intensity shapes this tonotopic organization. In animal models, increasing intensity shifts the cochlear traveling wave peak basally; however, physiological evidence for such intensity-dependent shifts in human cochlear processing is limited. Here, we performed simultaneous multielectrode electrocochleography recordings along the human scala tympani to characterize how cochlear place coding varies as a function of stimulus intensity. In subjects with preserved cochlear mechanics, including individuals with auditory …

Developmental Origins Of Exceptional Health And Survival: A Four-Generation Family Cohort Study, Matthew Thomas Keys, Søren Netra, Dorthe Almind Pedersen, Pernille Stemann Larsen, Alexander Kulminski, Mary F Feitosa, Mary Wojczynski, Michael Province, Kaare Christensen

2020-Current year OA Pubs

Descendants of longevity-enriched sibships demonstrate a broad health and survival advantage throughout the life course. However, little is known about manifestations during very early life. Here we show a pattern of lower risk of adverse early-life outcomes in third-generation grandchildren (N = 5637) of Danish longevity-enriched sibships compared to the general population, including infant mortality (Hazard Ratio = 0.53, 95% CI [0.36, 0.77]) and a range of neonatal health indicators. These associations in fourth-generation great-grandchildren (N = 14,908) were attenuated and less consistent (e.g., infant mortality, Hazard Ratio = 0.90, [0.70, 1.17]). Dilatory patterns across successive generations were independent of …

Tunable Tripcides Suppress Virulence Factor Secretion During Staphylococcus Aureus Infection And Kill Dormant Cells, Hasan Tükenmez, Taylor M Nye, Suzanne Hickerson, Chloe L P Obernuefemann, Jerome S Pinkner, Karen W Dodson, Michael G Caparon, Scott J Hultgren, Et Al.

2020-Current year OA Pubs

Antimicrobial resistance (AMR) in common bacterial pathogens, including methicillin-resistant

Inflammatory Markers In The Emergency Department And Ptsd Symptoms In The Aurora Study: A Longitudinal Cohort Study, Kristen Nishimi, Stacey L House, Et Al.

2020-Current year OA Pubs

BACKGROUND: Systemic inflammation is hypothesized to contribute to post-traumatic stress disorder (PTSD) vulnerability. Few studies have examined inflammation shortly after trauma as a predictor of later PTSD symptoms. We examined whether inflammation from the emergency department (ED) post-trauma is associated with PTSD symptom severity over the following 6 months.

METHODS: Our sample included 742 AURORA participants, a longitudinal cohort of patients in 29 EDs across the United States after a traumatic stressor, followed up to 6 months. Plasma cytokines were assessed from a study blood draw in the ED: an inflammatory index (standardized sum of generally pro-inflammatory markers interleukin [IL]-6, …

Nivolumab Plus Ipilimumab For Chemotherapy-Refractory Metastatic Castration-Resistant Prostate Cancer: Results From The Randomized Portion Of The Phase 2 Checkmate 650 Trial, Padmanee Sharma, Russell K Pachynski, Et Al.

2020-Current year OA Pubs

We report on the randomized portion of the phase 2, open-label CheckMate 650 trial (NCT02985957), in which docetaxel-experienced, biologically male patients with chemotherapy-refractory metastatic castration-resistant prostate cancer were randomized 2:2:1:2 to nivolumab 3 mg /kg plus ipilimumab 1 mg /kg (n = 73), nivolumab 1 mg /kg plus ipilimumab 3 mg /kg (n = 74), ipilimumab 3 mg /kg (n = 38), or cabazitaxel (n = 74). Primary endpoints were objective response rate and radiographic progression-free survival; key secondary endpoints included overall survival, prostate-specific antigen response rate, and safety. This portion of CheckMate 650 was not designed to statistically compare …

Gut Microbiota Modulation Of Regulatory Dna Elements Revealed By Massively Parallel Functional Characterization, Chadmirah Zaratiana, Adheet Ganesh, Yang E Li, Et Al.

2020-Current year OA Pubs

Cis-regulatory elements (CREs) are central to dynamic gene regulation in hepatocytes, yet most functional annotations derive from in vitro models that poorly capture physiological regulation. We systematically profiled 109,386 human liver-derived CREs using massively parallel reporter assays in hepatocytes under matched in vitro and in vivo conditions. In vivo-active functional CREs (fCREs) were enriched for H3K27ac and chromatin accessibility and were regulated by diverse transcription factors in the human liver. We further demonstrate that gut microbiota-derived signals modulate fCRE activity and target gene expression in vivo, in part via the KEAP1/NFE2L2 antioxidant pathway. Specific microbial metabolites directly altered the activity …

Genealogy-Based Trait Association With Locater Boosts Power At Loci With Allelic Heterogeneity, Xinxin Wang, Ryan Christ, Erica Young, Chul Joo Kang, Indraniel Das, Edward A Belter, Markku Laakso, Louis J M Aslett, David Steinsaltz, Nathan O Stitziel, Ira M Hall

2020-Current year OA Pubs

A key methodological challenge for genome-wide association studies is how to leverage haplotype diversity and allelic heterogeneity to improve trait association power, especially in noncoding regions where it is difficult to predict variant impacts and define functional units for variant aggregation. Genealogy-based association methods have the potential to bridge this gap by testing combinations of common and rare haplotypes based purely on their ancestral relationships. In parallel work, we have developed an efficient local ancestry inference engine and a novel statistical method (LOCATER) for combining signals present on different branches of a locus-specific haplotype tree. Here, we develop a genome-wide …

Mitochondrial Etf Insufficiency Drives Neoplastic Growth By Selectively Optimizing Cancer Bioenergetics, David Papadopoli, Sergej Djuranovic, Et Al.

2020-Current year OA Pubs

Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH …

Transcriptome Predictors Of Second Breast Events In Ductal Carcinoma In Situ: A Case‒Control Study Including Black And White Women, Aditi Hazra, Emma Berdan, Thomas Walsh, Sarah Humble, Jen Tappenden, Katherine Deschryver, Deborah Veis, Kiran Vij, Shannan Ho Sui, Graham A Colditz

2020-Current year OA Pubs

BACKGROUND: Black women diagnosed with ductal carcinoma in situ (DCIS) experience disproportionately higher risk of second breast cancer events (SBEs), including both ipsilateral and contralateral recurrences, yet remain underrepresented in molecular biomarker studies compared to non-Hispanic White women.

METHODS: We performed RNA sequencing on 200 archival DCIS samples from the Resource of Archival Breast Tissue cohort, including 33% self-reported Black women. We correlated transcriptomic and clinical data to identify predictors of SBEs. Cases (n = 100) who developed SBEs between 1999 and 2019 were matched 1:1 to controls (n = 100) on age, race, and margin status, who remained event-free …

Large-Scale Genetic Characterization Of Parkinson's Disease In The African And African Admixed Populations, Fulya Akçimen, Scott A Norris, Erin R Foster, Et Al.

2020-Current year OA Pubs

Elucidating the genetic contributions to Parkinson's disease aetiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11 827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among patients with Parkinson's disease, with a frequency of 4% in our case cohort. Of the 18 …

Recommendations Made And Accepted By A Telehealth-Enabled Antimicrobial Stewardship Program Implemented At Rural Veterans Affairs Medical Centers, Taissa A Bej, Jason P Burnham, Joshua D. Nordman, Et Al.

2020-Current year OA Pubs

BACKGROUND: To support Antimicrobial Stewardship programs (ASPs) as well as the clinical care of patients with infections, we disseminated and implemented a Videoconference Antimicrobial Stewardship Team (VAST) to connect multidisciplinary teams from rural Veterans Affairs (VA) medical centers with geographically distant ID experts. Here, we describe the clinical syndromes discussed and the response to recommendations made during VAST sessions.

METHODS: Between September 2021 to February 2024, eight ID consultants established VASTs with ten rural VAMCs, holding regularly scheduled videoconference sessions to discuss clinical cases and provide recommendations. Data were collected on patient demographics, clinical syndromes, and recommendations. Acceptance of recommendations …

Securepose: Automated Face Blurring And Human Movement Kinematics Extraction From Videos Recorded In Clinical Settings, Rishabh Bajpai, Bhooma Aravamuthan

2020-Current year OA Pubs

Movement disorder diagnosis often relies on expert evaluation of patient videos, but sharing these videos poses privacy risks. Current methods for de-identifying videos, such as blurring faces, are often manual, inconsistent, or inaccurate. Furthermore, these methods can compromise automated kinematics extraction-a valuable aid to movement analysis. To address these challenges, we developed SecurePose, open-source software that provides both reliable de-identification and automated body kinematic extraction from videos recorded in clinic settings using smartphones/tablets. We validated SecurePose on gait videos recorded in outpatient clinic visits of 116 children with cerebral palsy, assessing both the accuracy of its de-identification compared to the …

Androgen Loss Accelerates Brain Tumour Growth Via Hpa Axis Activation, Juyeun Lee, Joshua B Rubin, Et Al.

2020-Current year OA Pubs

Many cancers, including glioblastoma (GBM), show a male-biased incidence and associated worse outcomes

Adapt-On-Demand: Enabling Flexible And Scalable Adaptive Radiotherapy Through Workflow Automation, Sean Domal, Min Geon Choi, Justin Visak, Ruiqi Li, Taoran Li, Boon-Keng Kevin Teo, Xiaodong Zhao, Matthew Schmidt, Eric Laugeman, David Parsons, Yang Kyun Park, Shahed Badiyan, David Sher, Mu-Han Lin

2020-Current year OA Pubs

PURPOSE: CT-guided adaptive radiotherapy (CTgART) offers significant clinical benefits, but its utilization is often limited by resource demands and rigid workflows. This study presents a flexible and scalable "Adapt-on-Demand" (AOD) framework that integrates the adaptive capabilities of the Varian Ethos platform with the high-throughput IGRT delivery of the Varian Halcyon, supported by automated scripting.

METHODS: We developed an end-to-end dual-platform workflow that dynamically transitions between ART and IGRT delivery based on patient needs. Key components include Eclipse Scripting API (ESAPI) automation to streamline adapted plan ingestion from the Ethos Treatment Planning and Management System (TPMS) export directory, compatibility conversion for …

Use And Public Reporting Of Predetermined Change Control Plans For Ai-Enabled Medical Devices, Patryk A Dabek, Florence T Bourgeois, Ariel D Stern, Yi Zhu, Alexander O Everhart

2020-Current year OA Pubs

No abstract provided.

A Covalent Allosteric Molecular Glue Suppresses Nrf2-Dependent Cancer Growth, Nilotpal Roy, Ilah Bok, Harit Panda, Dhaval P Bhatt, Emily M Wilkerson, Soma Saeidi, Paul Zolkind, Michael B Major, Et Al.

2020-Current year OA Pubs

UNLABELLED: The NRF2 transcription factor is constitutively active in cancer, in which it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2 dependency and resistance to chemotherapy/radiotherapy (RT). In this study, we characterize VVD-065, a first-in-class NRF2 inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, NRF2 is rapidly degraded by the Kelch-like ECH-associated protein 1 (KEAP1)-cullin3 (CUL3) ubiquitin-ligase complex. VVD-065 specifically and covalently engages Cys151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported Cys151-directed compounds decrease KEAP1-CUL3 interactions …