Structural Determinants Research Articles

Structural Survey of Antigen Recognition by Synthetic Human Antibodies.

Synthetic antibody libraries have been used extensively to isolate and optimize antibodies. To generate these libraries, the immunological diversity and the antibody framework(s) that supports it outside of the binding regions are carefully designed/chosen to ensure favorable functional and biophysical properties. In particular, minimalist, single-framework synthetic libraries pioneered by our group have yielded a vast trove of antibodies to a broad array of antigens. Here, we review their systematic and iterative development to provide insights into the design principles that make them a powerful tool for drug discovery. In addition, the ongoing accumulation of crystal structures of antigen-binding fragment (Fab)-antigen complexes generated with synthetic antibodies enables a deepening understanding of the structural determinants of antigen recognition and usage of immunoglobulin sequence diversity, which can assist in developing new strategies for antibody and library optimization. Toward this, we also survey here the structural landscape of a comprehensive and unbiased set of 50 distinct complexes derived from these libraries and compare it to a similar set of natural antibodies with the goal of better understanding how each achieves molecular recognition and whether opportunities exist for iterative improvement of synthetic libraries. From this survey, we conclude that despite the minimalist strategies used for design of these synthetic antibody libraries, the overall structural interaction landscapes are highly similar to natural repertoires. We also found, however, some key differences that can help guide the iterative design of new synthetic libraries via the introduction of positionally tailored diversity.

Experimental and computational investigation of the effect of Hsc70 structural variants on inhibiting amylin aggregation

The misfolding and aggregation of human islet amyloid polypeptide (hIAPP), also known as amylin, have been implicated in the pathogenesis of type 2 diabetes (T2D). Heat shock proteins, specifically, heat shock cognate 70 (Hsc70), are molecular chaperones that protect against hIAPP misfolding and inhibits its aggregation. Nevertheless, there is an incomplete understanding of the mechanistic interactions between Hsc70 domains and hIAPP, thus limiting their potential therapeutic role in diabetes. This study investigates the inhibitory capacities of different Hsc70 variants, aiming to identify the structural determinants that strike a balance between efficacy and cytotoxicity. Our experimental findings demonstrate that the ATPase activity of Hsc70 is not a pivotal factor for inhibiting hIAPP misfolding. We underscore the significance of the C-terminal substrate-binding domain of Hsc70 in inhibiting hIAPP aggregation, emphasizing that the removal of the lid subdomain diminishes the inhibitory effect of Hsc70. Additionally, we employed atomistic discrete molecular dynamics simulations to gain deeper insights into the interaction between Hsc70 variants and hIAPP. Integrating both experimental and computational findings, we propose a mechanism by which Hsc70's interaction with hIAPP monomers disrupts protein-protein connections, primarily by shielding the β-sheet edges of the Hsc70-β-sandwich. The distinctive conformational dynamics of the alpha helices of Hsc70 potentially enhance hIAPP binding by obstructing the exposed edges of the β-sandwich, particularly at the β5-β8 region along the alpha helix interface. This, in turn, inhibits fibril growth, and similar results were observed following hIAPP dimerization. Overall, this study elucidates the structural intricacies of Hsc70 crucial for impeding hIAPP aggregation, improving our understanding of the potential anti-aggregative properties of molecular chaperones in diabetes treatment.

Disruption of Ca2+/calmodulin:KSR1 interaction lowers ERK activation.

KSR1, a key scaffold protein for the MAPK pathway, facilitates ERK activation upon growth factor stimulation. We recently demonstrated that KSR1 binds the Ca2+-binding protein calmodulin (CaM), thereby providing an intersection between KSR1-mediated and Ca2+ signaling. In this study, we set out to generate a KSR1 point mutant with reduced Ca2+/CaM binding in order to unravel the functional implications of their interaction. To do so, we solved the structural determinants of complex formation. Using purified fragments of KSR1, we showed that Ca2+/CaM binds to the CA3 domain of KSR1. We then used in silico molecular modeling to predict contact residues for binding. This approach identified two possible modes of interaction: (1) binding of extended Ca2+/CaM to a globular conformation of KSR1-CA3 via electrostatic interactions or (2) binding of collapsed Ca2+/CaM to α-helical KSR1-CA3 via hydrophobic interactions. Experimentally, site-directed mutagenesis of the predicted contact residues for the two binding models favored that where collapsed Ca2+/CaM binds to the α-helical conformation of KSR1-CA3. Importantly, replacing KSR1-Phe355 with Asp reduces Ca2+/CaM binding by 76%. The KSR1-F355D mutation also significantly impairs the ability of EGF to activate ERK, which reveals that Ca2+/CaM binding promotes KSR1-mediated MAPK signaling. This work, by uncovering structural insight into the binding of KSR1 to Ca2+/CaM, identifies a KSR1 single-point mutant as a bioreagent to selectively study the crosstalk between Ca2+ and KSR1-mediated signaling.

Internal and External Determinants of Capital Structure and Firm Value: Empirical Evidence from Property and Real Estate Firms in Indonesia

Houses, land, and property are vital human requirements, with increasing demands year after year. This is mostly due to Indonesia’s favorable population growth and economic development, which leads the demand for land and property to be even higher. However, this industry also experienced difficulties during the COVID-19 pandemic, which affected macroeconomic conditions. Therefore, this study aims to reinvestigate the role of internal and external factors on the capital structure and firm value of property and real estate firms listed on the IDX for the 2017-2021 period. In this study, the partial least squares structural equation modeling was used for the data analysis, whereas purposive sampling was used for company selection. The results showed that internal factors had a significant effect on capital structure and firm value, whereas external factors did not significantly impact capital structure and firm value. Lastly, capital structure is also proven to have no significant effect on firm value. These findings validate the signaling theory, where internal factors managed by the firm might produce a positive signal in the form of the firm’s future prospects so that it can become essential information for stakeholders. This study contributes to helping policymakers with various considerations and sets realistic expectations about the role of internal and external factors on the capital structure and firm values.
 Keywords: financial performance, macroeconomic, capital structure, firm value, signaling theory

Allosteric modulation of fluorescence revealed by hydrogen bond dynamics in a genetically encoded maltose biosensor.

Genetically encoded fluorescent biosensors (GEFBs) proved to be reliable tracers for many metabolites and cellular processes. In the simplest case, a fluorescent protein (FP) is genetically fused to a sensing protein which undergoes a conformational change upon ligand binding. This drives a rearrangement in the chromophore environment and changes the spectral properties of the FP. Structural determinants of successful biosensors are revealed only in hindsight when the crystal structures of both ligand-bound and ligand-free forms are available. This makes the development of new biosensors for desired analytes a long trial-and-error process. In the current study, we conducted μs-long all atom molecular dynamics (MD) simulations of a maltose biosensor in both the apo (dark) and holo (bright) forms. We performed detailed hydrogen bond occupancy analyses to shed light on the mechanism of ligand induced conformational change in the sensor protein and its allosteric effect on the chromophore environment. We find that two strong indicators for distinguishing bright and dark states of biosensors are due to substantial changes in hydrogen bond dynamics in the system and solvent accessibility of the chromophore.

Activity and Silencing of Transposable Elements in C. elegans

Since the discovery of transposable elements (TEs) in maize in the 1940s by Barbara McClintock transposable elements have been described as junk, as selfish elements with no benefit to the host, and more recently as major determinants of genome structure and genome evolution. TEs are DNA sequences that are capable of moving to new sites in the genome and making additional copies of themselves while doing so. To limit the propagation of TEs, host silencing mechanisms are directed at transposon-encoded genes that are required for mobilization. The mutagenic properties of TEs, the potential of TEs to form new genes and affect gene expression, together with the host silencing mechanisms, shape eukaryotic genomes and drive genome evolution. While TEs constitute more than half of the genome in many higher eukaryotes, transposable elements in the nematode C. elegans form a relatively small proportion of the genome (approximately 15%). Genetic studies of transposon silencing, and the discovery of RNA interference (RNAi) in C. elegans, propelled Caenorhabditis elegans (C. elegans) to the forefront of studies of RNA-based mechanisms that silence TEs. Here, I will review the transposable elements that are present and active in the C. elegans genome, and the host defense mechanisms that silence these elements.

Geospatial Correlations and Variations in Child Mortality and Stunting in South Africa: Evaluating Distal vs Structural Determinants

South Africa has one of the highest child mortality and stunting rates in the world. Flexible geoadditive models were used to investigate the geospatial variations in child mortality and stunting in South Africa. We used consecutive rounds of national surveys (2008-2017). The child mortality declined from 31% to 24% over time. Lack of medical insurance, black ethnicity, low-socioeconomic conditions, and poor housing conditions were identified as the most significant correlates of child mortality. The model predicted degrees of freedom which was estimated as 19.55 (p<0.001), provided compelling evidence for sub-geographical level variations in child mortality which ranged from 6% to 35% across the country. Population level impact of the distal characteristics on child mortality and stunting exceeded that of other risk factors. Geospatial analysis can help in monitoring trends in child mortality over time and in evaluating the impact of health interventions.

Social and Spatial Determinants of the Spatial Structure of Crime in Szczecin, Poland

Social and Spatial Determinants of the Spatial Structure of Crime in Szczecin, Poland

Accurate Characterization of Binding Kinetics and Allosteric Mechanisms for the HSP90 Chaperone Inhibitors Using AI-Augmented Integrative Biophysical Studies

Accurate Characterization of Binding Kinetics and Allosteric Mechanisms for the HSP90 Chaperone Inhibitors Using AI-Augmented Integrative Biophysical Studies

Using generative AI to investigate medical imagery models and datasets

BackgroundAI models have shown promise in performing many medical imaging tasks. However, our ability to explain what signals these models have learned is severely lacking. Explanations are needed in order to increase the trust of doctors in AI-based models, especially in domains where AI prediction capabilities surpass those of humans. Moreover, such explanations could enable novel scientific discovery by uncovering signals in the data that aren’t yet known to experts. MethodsIn this paper, we present a workflow for generating hypotheses to understand which visual signals in images are correlated with a classification model’s predictions for a given task. This approach leverages an automatic visual explanation algorithm followed by interdisciplinary expert review. We propose the following 4 steps: (i) Train a classifier to perform a given task to assess whether the imagery indeed contains signals relevant to the task; (ii) Train a StyleGAN-based image generator with an architecture that enables guidance by the classifier (“StylEx”); (iii) Automatically detect, extract, and visualize the top visual attributes that the classifier is sensitive towards. For visualization, we independently modify each of these attributes to generate counterfactual visualizations for a set of images (i.e. what the image would look like with the attribute increased or decreased); (iv) Formulate hypotheses for the underlying mechanisms, to stimulate future research. Specifically, present the discovered attributes and corresponding counterfactual visualizations to an interdisciplinary panel of experts so that hypotheses can account for social and structural determinants of health (e.g. whether the attributes correspond to known patho-physiological or socio-cultural phenomena, or could be novel discoveries). FindingsTo demonstrate the broad applicability of our approach, we present results on eight prediction tasks across three medical imaging modalities – retinal fundus photographs, external eye photographs, and chest radiographs. We showcase examples where many of the automatically-learned attributes clearly capture clinically known features (e.g., types of cataract, enlarged heart), and demonstrate automatically-learned confounders that arise from factors beyond physiological mechanisms (e.g., chest X-ray underexposure is correlated with the classifier predicting abnormality, and eye makeup is correlated with the classifier predicting low hemoglobin levels). We further show that our method reveals a number of physiologically plausible, previously-unknown attributes based on the literature (e.g., differences in the fundus associated with self-reported sex, which were previously unknown). InterpretationOur approach enables hypotheses generation via attribute visualizations and has the potential to enable researchers to better understand, improve their assessment, and extract new knowledge from AI-based models, as well as debug and design better datasets. Though not designed to infer causality, importantly, we highlight that attributes generated by our framework can capture phenomena beyond physiology or pathophysiology, reflecting the real world nature of healthcare delivery and socio-cultural factors, and hence interdisciplinary perspectives are critical in these investigations. Finally, we plan to release code to enable researchers to train their own StylEx models and analyze their predictive tasks of interest, and use the methodology presented in this paper for responsible interpretation of the revealed attributes. FundingGoogle

Structural insights into the bifunctional enzyme human FAD synthase.

Human flavin adenine dinucleotide synthase (hFADS) is a bifunctional, multi-domain enzyme that exhibits both flavin mononucleotide adenylyltransferase and pyrophosphatase activities. Here we report the crystal structure of full-length hFADS2 and its C-terminal PAPS domain in complex with flavin adenine dinucleotide (FAD), and dissect the structural determinants underlying the contribution of each individual domain, within isoforms 1 and 2, to each of the two enzymatic activities. Structural and functional characterization performed on complete or truncated constructs confirmed that the C-terminal domain tightly binds FAD and catalyzes its synthesis, while the combination of the N-terminal molybdopterin-binding and KH domains is the minimal essential substructure required for the hydrolysis of FAD and other ADP-containing dinucleotides. hFADS2 associates in a stable C2-symmetric dimer, in which the packing of the KH domain of one protomer against the N-terminal domain of the other creates the adenosine-specific active site responsible for the hydrolytic activity.

Capital Structure Determinants in Pakistan's Textile Industry Unravelling the Pecking Order vs. Trade-Off Debate

Capital Structure Determinants in Pakistan's Textile Industry Unravelling the Pecking Order vs. Trade-Off Debate

THE BURGEONING BURDEN OF PERINATAL MENTAL HEALTH IN LOWER MIDDLE-INCOME COUNTRIES

THE BURGEONING BURDEN OF PERINATAL MENTAL HEALTH IN LOWER MIDDLE-INCOME COUNTRIES

Study of Hydration Repulsion of Zwitterionic Polymer Brushes Resistant to Protein Adhesion through Molecular Simulations.

The fabrication of antifouling zwitterionic polymer brushes represents a leading approach to mitigate nonspecific adhesion on the surfaces of medical devices. This investigation seeks to elucidate the correlation between the material composition and structural attributes of these polymer brushes in preventing protein adhesion. To achieve this goal, we modeled three different zwitterionic brushes, namely, carboxybetaine methacrylate (CBMA), sulfobetaine methacrylate (SBMA), and (2-(methacryloyloxy)ethyl)-phosphorylcholine (MPC). The simulations revealed that elevating the grafting density enhances the structural stability, hydration strength, and resistance to protein adhesion exhibited by the polymer brushes. PCBMA manifests a more robust hydration layer, while PMPC demonstrates the slightest interaction with proteins. In a comprehensive evaluation, PSBMA polymer brushes emerged as the best choice with superior stability, enhanced protein repulsion, and minimally induced protein deformation, resulting in effective resistance to nonspecific adhesion. The high-density SBMA polymer brushes significantly reduce the level of protein adhesion in AFM testing. In addition, we have pioneered the quantitative characterization of hydration repulsion in polymer brushes by analyzing the hydration repulsion characteristics at different materials and graft densities. In summary, our study provides a nuanced understanding of the material and structural determinants influencing the capacity of zwitterionic polymer brushes to thwart protein adhesion. Additionally, it presents a quantitative elucidation of hydration repulsion, contributing to the advancement and application of antifouling polymer brushes.

How patients experience respect in healthcare: findings from a qualitative study among multicultural women living with HIV

BackgroundRespect is essential to providing high quality healthcare, particularly for groups that are historically marginalized and stigmatized. While ethical principles taught to health professionals focus on patient autonomy as the object of respect for persons, limited studies explore patients’ views of respect. The purpose of this study was to explore the perspectives of a multiculturally diverse group of low-income women living with HIV (WLH) regarding their experience of respect from their medical physicians.MethodsWe analyzed 57 semi-structured interviews conducted at HIV case management sites in South Florida as part of a larger qualitative study that explored practices facilitating retention and adherence in care. Women were eligible to participate if they identified as African American (n = 28), Hispanic/Latina (n = 22), or Haitian (n = 7). They were asked to describe instances when they were treated with respect by their medical physicians. Interviews were conducted by a fluent research interviewer in either English, Spanish, or Haitian Creole, depending on participant’s language preference. Transcripts were translated, back-translated and reviewed in entirety for any statements or comments about “respect.” After independent coding by 3 investigators, we used a consensual thematic analysis approach to determine themes.ResultsResults from this study grouped into two overarching classifications: respect manifested in physicians’ orientation towards the patient (i.e., interpersonal behaviors in interactions) and respect in medical professionalism (i.e., clinic procedures and practices). Four main themes emerged regarding respect in provider’s orientation towards the patient: being treated as a person, treated as an equal, treated without blame or prejudice, and treated with concern/emotional support. Two main themes emerged regarding respect as evidenced in medical professionalism: physician availability and considerations of privacy.ConclusionsFindings suggest a more robust conception of what ‘respect for persons’ entails in medical ethics for a diverse group of low-income women living with HIV. Findings have implications for broadening areas of focus of future bioethics education, training, and research to include components of interpersonal relationship development, communication, and clinic procedures. We suggest these areas of training may increase respectful medical care experiences and potentially serve to influence persistent and known social and structural determinants of health through provider interactions and health care delivery.

What explain capital structure determinants choices of Shariah firms?

This study aims to discover key capital structure determinants for the entire Shariah firms operating in dissimilar contexts. Moreover, it also estimates the adjustment speed for these firms to maintain targeted capital structures at all times. For this purpose, 321 Shariah firms that are operational in Saudi Arabia, Pakistan, the UAE, and Indonesia are nominated. The empirical analysis is conducted using 11 years, i.e., 2011-2021, of balanced Panel Data. The debt-to-asset and debt-to-equity ratios are used as variables of interest, whereas the asset tangibility ratio, current ratio, return on equity, size, non-debt-tax shield, inflation, and gross domestic product are used as explanatory variables. The robust estimator, i.e., Generalized Method of Moments (GMM), is executed to perform the analysis. The results show that the most important factors for Shariah-tagged firms are inflation, the gross domestic product, the asset ratio, the return on equity, the non-debt tax shield, and the lagged dependent variables. The important role of asset tangibility, lagged variables, and the presence of adjustment speed postulate that Shariah-tagged firms are following the provided guidelines of Dynamic Trade-Off theory to preserve capital structure. The findings are a new contribution to the limited empirical inquiries of Shariah firms’ capital structure and a fresh addition to Islamic Finance literature. Besides, the outcomes are also helpful for policymakers and assist them in developing an optimal model of capital structure for Shariah-tagged firms that decreases overall capital costs and enhances these firms’ market value.

Structural determinants of the direct inhibition of GIRK channels by Sigma-1 receptor antagonist

G-protein-gated inward rectifier K+ (GIRK) channels play a critical role in the regulation of the excitability of cardiomyocytes and neurons and include GIRK1, GIRK2, GIRK3 and GIRK4 subfamily members. BD1047 dihydrobromide (BD1047) is one of the representative antagonists of multi-functional Sigma-1 receptor (S1R). In the analysis of the effect of BD1047 on the regulation of Gi-coupled receptors by S1R using GIRK channel as an effector, we observed that BD1047, as well as BD1063, directly inhibited GIRK currents even in the absence of S1R and in a voltage-independent manner. Thus, we aimed to clarify the effect of BD1047 on GIRK channels and identify the structural determinants. By electrophysiological recordings in Xenopus oocytes, we observed that BD1047 directly inhibited GIRK channel currents, producing a much stronger inhibition of GIRK4 compared to GIRK2. It also inhibited ACh-induced native GIRK current in isolated rat atrial myocytes. Chimeric and mutagenesis studies of GIRK2 and GIRK4 combined with molecular docking analysis, demonstrated the importance of Leu77 and Leu84 within the cytoplasmic, proximal N-terminal region and Glu147 within the pore forming region of GIRK4 for inhibition by BD1047. The activator of GIRK channels, ivermectin, competed with BD1047 at Leu77 on GIRK4. This study provides us with a novel inhibitor of GIRK channels and information for developing pharmacological treatments for GIRK4 associated diseases.

Engineering quorum quenching acylases with improved kinetic and biochemical properties.

Many Gram-negative bacteria use N-acyl-L-homoserine lactone (AHL) signals to coordinate phenotypes such as biofilm formation and virulence factor production. Quorum-quenching enzymes, such as AHL acylases, chemically degrade these molecules which prevents signal reception by bacteria and inhibits undesirable biofilm-related traits. These capabilities make acylases appealing candidates for controlling microbes, yet candidates with high activity levels and substrate specificity and that are capable of being formulated into materials are needed. In this work, we undertook engineering efforts against two AHL acylases, PvdQ and MacQ, to generate these improved properties using the Protein One-Stop Shop Server. The engineering of acylases is complicated by low-throughput enzymatic assays. Alleviating this challenge, we report a time-course kinetic assay for AHL acylases that monitors the real-time production of homoserine lactone. Using the assay, we identified variants of PvdQ that were significantly stabilized, with melting point increases of up to 13.2°C, which translated into high resistance against organic solvents and increased compatibility with material coatings. While the MacQ mutants were unexpectedly destabilized, they had considerably improved kinetic properties, with >10-fold increases against N-butyryl-L-homoserine lactone and N-hexanoyl-L-homoserine lactone. Accordingly, these changes resulted in increased quenching abilities using a biosensor model and greater inhibition of virulence factor production of Pseudomonas aeruginosa PA14. While the crystal structure of one of the MacQ variants, M1, did not reveal obvious structural determinants explaining the observed changes in kinetics, it allowed for the capture of an acyl-enzyme intermediate that confirms a previously hypothesized catalytic mechanism of AHL acylases.

Abstract 5785: Shedding light on PARP1-E2F1 interaction by Cryo-EM

Abstract Cell division is orchestrated by a complex network of interactions between proteins involved in numerous signaling pathways that control cell proliferation. One of these main players is the E2F family of transcription factors. The role of these key players is to regulate the expression of several genes important in cell proliferation, particularly those involved in progression through G1 and into the S-phase of the cell cycle. In fact, cell cycle deregulation is a hallmark of cancer, and multiple studies have highlighted the critical role of E2F hyperactivation in tumor progression, angiogenesis, and metastasis. However, targeting a master regulator of cell growth will also have a pernicious effect on non-cancerous cells, thus limiting its applications. In order to overwhelm these restrictions, we propose a therapeutic approach in which E2F transcriptional activity is specifically reduced in cells with hyperactivation of the pathway, such as cancer cells.We and others have shown that poly (ADP-ribose) polymerase 1 (PARP1) is a transcriptional co-activator of E2F1 and, owing to this, loss of PARP results in cell cycle re-regulation and reduction of tumor growth. Interestingly, this effect of PARP1 does not depend on its enzymatic activity, thus opening a completely new strategic approach. Furthermore, considering that most oncogenic processes are associated with cell cycle deregulation, disruption of PARP1-E2F1 interaction could provide a new therapeutic target with a wide spectrum of indications in cancer. Currently, we lack comprehensive structural details regarding the PARP-1/E2F1 protein-protein interaction. To address this, we used cryo-EM to investigate both the standalone structure of PARP1 (full length) and its interaction with E2F1. This approach yielded high-resolution structural insights into the PARP1-E2F1 complex, enabling precise identification of the protein-protein interaction interface (PPI). Through this exploration of structural and molecular determinants governing this interaction, we aim to develop innovative strategies for designing drugs targeted at disrupting this complex. This work was supported by Agencia Estatal de Investigación (AEl/10.13039/501100011033), Xunta de Galicia (GPC GI-1862, ED431B 2020/26; ED431G 2019/02) and European Regional Development Fund-ERDF. Citation Format: Pablo Iglesias, Ester Casajus-Pelegay, Maria Moreno-Morcillo, Lara González-Rendo, Laura Porres-Ventin, Victor M. Arce, Rafael Fernandez-Leiro, Jose A. Costoya. Shedding light on PARP1-E2F1 interaction by Cryo-EM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5785.

Higher area deprivation index is associated with poorer local control and overall survival in non-metastatic nasopharyngeal carcinoma.

Neighborhood socioeconomic deprivation impacts outcomes in various cancers. We examined this association in nasopharyngeal carcinoma (NPC) patients using the area deprivation index (ADI). We conducted a single-institution retrospective cohort study on NPC patients treated with definitive radiotherapy from 1980 to 2023. ADI was used as the primary exposure measure. Higher ADI indicates higher levels of socioeconomic deprivation. Of 561 patients, those with higher ADI (6-10 vs. 1-5) presented more commonly with AJCC stage III/IV compared to I/II (87% vs. 76%, p = 0.03). Increasing ADI decile score correlated with poorer overall survival (HR 1.14, 95% CI 1.01-1.28, p = 0.04). Local control was worse in patients from the most deprived quartile in the cohort ADI 5-10 (HR 2.11, 95% CI 1.01-4.41, p = 0.05). NPC patients from more disadvantaged neighborhoods undergoing radiotherapy had worse local control and survival outcomes. Interventions to address structural determinants of health and neighborhood disparities may improve these outcomes.