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At least 1,027 records · Page 57
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Lung health in era of climate change and dust storms

Highlights: • Dust storms provide a vital role on Earth. • The health impact of dust storms is principally determined by the particle size. • The immune system plays a vital role in dust exposure. • Association between dust and sarcoidosis has been proposed. • Prevention and reduction of particle exposure is of paramount importance. Dust storms are strong winds which lead to particle exposure over extensive areas. These storms influence air quality on both a local and global scale which lead to both short and long-term effects. The frequency of dust storms has been on the rise during the last decade. Forecasts suggest that their incidence will increase as a response to the effects of climate change and anthropogenic activities. Elderly people, young children, and individuals with chronic cardiopulmonary diseases are at the greatest risk for health effects of dust storms. A wide variety of infectious and non-infectious diseases have been associated with dust exposure. Influenza A virus, pulmonary coccidioidomycosis, bacterial pneumonia, and meningococcal meningitis are a few examples of dust-related infectious diseases. Among non-infectious diseases, chronic obstructive pulmonary disease, asthma, sarcoidosis and pulmonary fibrosis have been associated with dust contact. Here, we review two molecular mechanisms of dust induced lung disease for asthma and sarcoidosis. We can also then further understand the mechanisms by which dust particles disturb airway epithelial and immune cells.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Preclinical characterization of Pan-NKG2D ligand-binding NKG2D receptor decoys

NKG2D and its ligands are critical regulators of protective immune responses controlling infections and cancer, defining a crucial immune signaling axis. Current therapeutic efforts targeting this axis almost exclusively aim at enhancing NKG2D-mediated effector functions. However, this axis can drive disease processes when dysregulated, in particular, driving stem-like cancer cell reprogramming and tumorigenesis through receptor/ligand self-stimulation on tumor cells. Despite complexities with its structure and biology, we developed multiple novel engineered proteins that functionally serve as axis-blocking NKG2D “decoys” and report biochemical, structural, in vitro , and in vivo evaluation of their functionality.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell–Mediated Killing

Purpose: To provide the foundation for combining immunotherapy to induce tumor antigen–specific T cells with proton radiation therapy to exploit the activity of those T cells. Methods and Materials: Using cell lines of tumors frequently treated with proton radiation, such as prostate, breast, lung, and chordoma, we examined the effect of proton radiation on the viability and induction of immunogenic modulation in tumor cells by flow cytometric and immunofluorescent analysis of surface phenotype and the functional immune consequences. Results: These studies show for the first time that (1) proton and photon radiation induced comparable up-regulation of surface molecules involved in immune recognition (histocompatibility leukocyte antigen, intercellular adhesion molecule 1, and the tumor-associated antigens carcinoembryonic antigen and mucin 1); (2) proton radiation mediated calreticulin cell-surface expression, increasing sensitivity to cytotoxic T-lymphocyte killing of tumor cells; and (3) cancer stem cells, which are resistant to the direct cytolytic activity of proton radiation, nonetheless up-regulated calreticulin after radiation in a manner similar to non-cancer stem cells. Conclusions: These findings offer a rationale for the use of proton radiation in combination with immunotherapy, including for patients who have failed radiation therapy alone or have limited treatment options.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Safety and Efficacy of Radiation Therapy in Advanced Melanoma Patients Treated With Ipilimumab

Purpose: Ipilimumab and radiation therapy (RT) are standard treatments for advanced melanoma; preclinical models suggest the potential for synergy. However, limited clinical information exists regarding safety and optimal timing of the combination. Methods and Materials: We reviewed the records of consecutive patients with unresectable stage 3 or 4 melanoma treated with ipilimumab. Patients were categorized as having received RT or not. Differences were estimated between these 2 cohorts. Results: We identified 88 patients treated with ipilimumab. At baseline, the ipilimumab-plus-RT group (n=44) had more unfavorable characteristics. Despite this, overall survival, progression-free survival, and both immune-related and non–immune-related toxicity were not statistically different (P=.67). Patients who received ipilimumab before RT had an increased duration of irradiated tumor response compared with patients receiving ipilimumab after RT (74.7% vs 44.8% at 12 months; P=.01, log-rank test). In addition, patients receiving ablative RT had non–statistically significantly improved median overall survival (19.6 vs 10.2 months), as well as 6-month (95.1% vs 72.7%) and 12-month (79.7% vs 48.5%) survival rates, compared with those treated with conventionally fractionated RT. Conclusions: We found that both ablative and conventionally fractionated RT can be safely administered with ipilimumab without a clinically apparent increase in toxicity. Patients who received ipilimumab before RT had an increased duration of irradiated tumor response.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Targeting Myeloid-derived Suppressor Cells and Programmed Death Ligand 1 Confers Therapeutic Advantage of Ablative Hypofractionated Radiation Therapy Compared With Conventional Fractionated Radiation Therapy

Ablative hypofractionated radiation therapy (AHFRT) presents a therapeutic advantage compared with conventional fractionated radiation therapy (CFRT) for primary and oligometastatic cancers. However, the underlying mechanisms remain largely unknown. In the present study, we compared the immune alterations in response to AHFRT versus CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Stereotactic Ablative Radiation Therapy Induces Systemic Differences in Peripheral Blood Immunophenotype Dependent on Irradiated Site

Despite the strong interest in combining stereotactic ablative radiation therapy (SAR) with immunotherapy, limited data characterizing the systemic immune response after SAR are available. We hypothesized that the systemic immune response to SAR would differ by irradiated site owing to inherent differences in the microenvironment of various organs.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Dose-limiting Urinary Toxicity With Pembrolizumab Combined With Weekly Hypofractionated Radiation Therapy in Bladder Cancer

There is currently significant interest in the potential benefits of combining radiation and immune checkpoint blockade (ICB) to stimulate both regional and distant abscopal immune responses. In melanoma and lung cancer, patients who have received radiation therapy during ICB appear to have prolonged survival. The PLUMMB trial (Pembrolizumab in Muscle-invasive/Metastatic Bladder cancer) (NCT02560636) is a phase I study to test the tolerability of a combination of weekly radiation therapy with pembrolizumab in patients with metastatic or locally advanced urothelial cancer of the bladder. In the first dose-cohort, patients received pembrolizumab 100 mg 3-weekly, starting 2 weeks before commencing weekly adaptive bladder radiation therapy to a dose of 36 Gy in 6 fractions. The first dose-cohort was stopped after 5 patients, having met the predefined definition of dose-limiting toxicity. Three patients experienced grade 3 urinary toxicities, 2 of which were attributable to therapy. One patient experienced a grade 4 rectal perforation. In view of these findings, the trial has been paused and the protocol will be amended to reduce radiation therapy dose per fraction. The authors advise caution to those combining radiation therapy and ICB, particularly when radiation therapy is given at high dose per fraction for pelvic tumours. The PLUMMB trial met the protocol-defined definition of dose-limiting toxicity and will be amended to reduce radiation therapy dose.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Targeted Alpha Particle Therapy Remodels the Tumor Microenvironment and Improves Efficacy of Immunotherapy

The tumor microenvironment (TME) can severely impair immunotherapy efficacy by repressing the immune system. In a multiple myeloma (MM) murine model, we investigated the impact of targeted alpha particle therapy (TAT) on the immune TME. TAT was combined with an adoptive cell transfer of CD8 T cells (ACT), and the mechanisms of action of this combination were assessed at the tumor site.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

Investigating the FLASH Effect in a Rat Brain Organotypic Model With a Novel High-Energy Electron Beam

Ultrahigh dose rate (FLASH) radiation therapy is reported to reduce normal tissue toxicity while maintaining tumor control; however, mechanism(s) remain obscure. To study FLASH mechanisms in brain tissue, we developed a novel experimental platform featuring a specialized high-energy electron linear accelerator, High Intensity Gamma Ray Source (HIGS), paired with an organotypic ex vivo brain metastasis model. We varied interpulse spacing to modulate the mean dose rate (MDR) of our unique 35 MeV electron beam, while maintaining extremely high instantaneous dose rate (IDR). We characterized dosimetry and targeting accuracy of the FLASH beam with film dosimetry. We combined this FLASH beam with an organotypic rat brain slice/breast carcinoma coculture model of brain metastasis to assess effects on normal and neoplastic tissues. Live-cell and bioluminescence imaging demonstrated cancer cell growth effects, whereas normal tissue responses and immune activation were assessed using live-cell imaging, cytokine profiles, and confocal microscopy. Here, we performed comparison experiments with 20 MeV electrons from a Varian clinical linear accelerator (VCLA) using conventional dose rates. The highest IDR of the FLASH beam to date was 20.7 ± 0.6 MGy/s, with maximum MDR of 20.7 MGy/s delivered in 1 pulse of 1 µs duration. Beam targeting was accurate to <1 mm and reproducible. HIGS-FLASH and VCLA dose rates equivalently decreased cancer cell growth. HIGS-FLASH irradiation significantly increased tumor necrosis factor α and fractalkine levels and confocal microscopy revealed distinct changes in microglial morphology slices suggesting microglia activation. Our novel experimental platform produces extremely high dose rates and rapid normal/neoplastic tissue readouts for mechanistic research into the effects of FLASH radiation in the brain. HIGS-FLASH irradiation induces comparable cancer cell growth inhibition but differential effects on cytokines and microglial morphology, suggesting that acute innate immune responses may be involved in FLASH normal tissue effects in the brain.

Kay, Tyler V. [Duke University, Durham, NC (United↗
DOE OSTI2022

Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes

Increased immune evasion by SARS-CoV-2 variants of concern highlights the need for new therapeutic neutralizing antibodies. Immunization with nanoparticles co-displaying spike receptor-binding domains (RBDs) from eight sarbecoviruses (mosaic-8 RBD-nanoparticles) efficiently elicits cross-reactive polyclonal antibodies against conserved sarbecovirus RBD epitopes. Here, we identified monoclonal antibodies (mAbs) capable of cross-reactive binding and neutralization of animal sarbecoviruses and SARS-CoV-2 variants by screening single mouse B cells secreting IgGs that bind two or more sarbecovirus RBDs. Single-particle cryo-EM structures of antibody-spike complexes, including a Fab-Omicron complex, mapped neutralizing mAbs to conserved class 1/4 RBD epitopes. Structural analyses revealed neutralization mechanisms, potentials for intra-spike trimer cross-linking by IgGs, and induced changes in trimer upon Fab binding. In addition, we identified a mAb-resembling Bebtelovimab, an EUA-approved human class 3 anti-RBD mAb. These results support using mosaic RBD-nanoparticle vaccination to generate and identify therapeutic pan-sarbecovirus and pan-variant mAbs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Potent transmission-blocking monoclonal antibodies from naturally exposed individuals target a conserved epitope on Plasmodium falciparum Pfs230

Pfs230 is essential for Plasmodium falciparum transmission to mosquitoes and is the protein targeted by the most advanced malaria-transmission-blocking vaccine candidate. Prior understanding of functional epitopes on Pfs230 is based on two monoclonal antibodies (mAbs) with moderate transmission-reducing activity (TRA), elicited from subunit immunization. Here, we screened the B cell repertoire of two naturally exposed individuals possessing serum TRA and identified five potent mAbs from sixteen Pfs230 domain-1-specific mAbs. Structures of three potent and three low-activity antibodies bound to Pfs230 domain 1 revealed four distinct epitopes. Highly potent mAbs from natural infection recognized a common conformational epitope that is highly conserved across P. falciparum field isolates, while antibodies with negligible TRA derived from natural infection or immunization recognized three distinct sites. Our study provides molecular blueprints describing P. falciparum TRA, informed by contrasting potent and non-functional epitopes elicited by natural exposure and vaccination.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

A proteome-wide assessment of the oxidative stress paradigm for metal and metal-oxide nanomaterials in human macrophages

Responsible implementation of engineered nanomaterials (ENMs) into commercial applications is an important societal issue, driving demand for new approaches for rapid and comprehensive evaluation of their bioactivity and safety. An essential part of any research focused on identifying potential hazard of ENMs is the appropriate selection of biological endpoints to evaluate. Herein, we use a tiered strategy employing both targeted biological assays and untargeted quantitative proteomics to elucidate the biological responses of human macrophages across a library of metal/metal oxide ENMs, raised as priority ENMs for investigation by NIEHS’s Nanomaterial Health Implications Research (NHIR) program. Our results show that quantitative cellular proteome profiles readily distinguish ENM types based on their cytotoxic potential according to induction of biological processes and pathways involved in the cellular antioxidant response, TCA cycle, oxidative stress, endoplasmic reticulum stress, and immune responses as major processes impacted. Interestingly, pathway analysis of differentially abundant proteins also revealed new cell processes that were influenced by all ENMs independent of cytotoxic potential. These included pathways previously implicated as cellular adaptive mechanisms to low levels of oxidative stress, including cell adhesion, protein translation and protein targeting pathways. Unsupervised clustering of all data revealed the most striking proteome changes that differentiated ENM classes involved a small subset of proteins involved in the oxidative stess response (HMOX1), protein chaperone functions (HS71B, DNJB1), and autophagy (SQSTM), providing a potential new panel of markers of ENM-induced cell stress. To our knowledge, the results represent the most comprehensive profiling of the biological responses to a library of ENMs conducted using quantitative mass spectrometry-based proteomics. The results provide a basis to identify the patterns of a diverse set of cellular pathways and cell processes impacted by ENM exposure in an important immune cell type, laying the foundation for multivariate, pathway-level structure activity assessments of ENMs in the future.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Kinetic analysis of Cas12a and Cas13a RNA-Guided nucleases for development of improved CRISPR-Based diagnostics

Bacterial CRISPR systems provide acquired immunity against invading nucleic acids by activating RNA-programmable RNases and DNases. Cas13a and Cas12a enzymes bound to CRISPR RNA (crRNA) recognize specific nucleic acid targets, initiating cleavage of the targets as well as non-target (trans) nucleic acids. Here, we examine the kinetics of single-turnover target and multi-turnover trans-nuclease activities of both enzymes. High-turnover, non-specific Cas13a trans-RNase activity is coupled to rapid binding of target RNA. By contrast, low-turnover Cas12a trans-nuclease activity is coupled to relatively slow cleavage of target DNA, selective for DNA over RNA, indifferent to base identity, and preferential for single-stranded substrates. Combining multiple crRNA increases detection sensitivity of targets, an approach we use to quantify pathogen DNA in samples from patients suspected of Buruli ulcer disease. Results reveal that these enzymes are kinetically adapted to play distinct roles in bacterial adaptive immunity and show how kinetic analysis can be applied to CRISPR-based diagnostics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Network analysis uncovers the communication structure of SARS-CoV-2 spike protein identifying sites for immunogen design

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered myriad efforts to understand the structure and dynamics of this complex pathogen. The spike glycoprotein of SARS-CoV-2 is a significant target for immunogens as it is the means by which the virus enters human cells, while simultaneously sporting mutations responsible for immune escape. These functional and escape processes are regulated by complex molecular-level interactions. Our study presents quantitative insights on domain and residue contributions to allosteric communication, immune evasion, and local- and global-level control of functions through the derivation of a weighted graph representation from all-atom MD simulations. Focusing on the ancestral form and the D614G-variant, we provide evidence of the utility of our approach by guiding the selection of a mutation that alters the spike’s stability. Taken together, the network approach serves as a valuable tool to evaluate communication “hot-spots” in proteins to guide design of stable immunogens.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Apolipoprotein A5 reduces clearance of VLDL by altering apolipoprotein E content

Apolipoprotein A-V (APOA5) is a critical regulator of circulating triglyceride (TG) levels. Its deletion leads to elevated plasma TG concentrations by altering the metabolism of very low-density lipoprotein (VLDL) particles in vivo. One way APOA5 exerts its effects is through modulation of lipoprotein lipase (LPL) activity, specifically by disrupting inhibitory interactions between LPL and angiopoietin-like proteins (ANGPTLs). However, the impact of APOA5 on VLDL composition and its potential to alter VLDL metabolism in other ways remains poorly understood. To address this, we investigated the influence of APOA5 on the VLDL proteome, LPL activation, and hepatic remnant uptake. Using VLDL from Apoa5 knockout (KO) and wild-type (WT) mice, we found no evidence that APOA5 directly enhances LPL activity in purified or plasma systems. However, VLDL from Apoa5 K mice was cleared significantly more slowly by cultured hepatocytes. Proteomics experiments from two independent laboratories identified consistent depletion of 17 proteins involved in lipoprotein metabolism, inflammation, and immune response in Apoa5 KO VLDL, including APOE and serum amyloid A1 (SAA1). Remarkably, reintroduction of recombinant mouse APOA5 to the KO plasma partially restored the WT VLDL proteome, including APOE, and normalized VLDL uptake by hepatocytes without altering LPL lipolysis. These findings reveal that APOA5 influences hepatic clearance of VLDL remnants by modulating particle composition, particularly APOE content. This study expands the functional scope of APOA5 in TG metabolism and underscores its role in VLDL remodeling and remnant clearance, offering new insights with implications for understanding hypertriglyceridemia and its roles in inflammation and immune response.

LPL↗
DOE OSTI2016

Mining the human urine proteome for monitoring renal transplant injury

The human urinary proteome reflects systemic and inherent renal injury perturbations and can be analyzed to harness specific biomarkers for different kidney transplant injury states. 396 unique urine samples were collected contemporaneously with an allograft biopsy from 396 unique kidney transplant recipients. Centralized, blinded histology on the graft was used to classify matched urine samples into categories of acute rejection (AR), chronic allograft nephropathy (CAN), BK virus nephritis (BKVN), and stable graft (STA). Liquid chromatography–mass spectrometry (LC-MS) based proteomics using iTRAQ based discovery (n=108) and global label-free LC-MS analyses of individual samples (n=137) for quantitative proteome assessment were used in the discovery step. Selected reaction monitoring (SRM) was applied to identify and validate minimal urine protein/peptide biomarkers to accurately segregate organ injury causation and pathology on unique urine samples (n=151). A total of 958 proteins were initially quantified by iTRAQ, 87% of which were also identified among 1574 urine proteins detected in LC-MS validation. 103 urine proteins were significantly (p<0.05) perturbed in injury and enriched for humoral immunity, complement activation, and lymphocyte trafficking. A set of 131 peptides corresponding to 78 proteins were assessed by SRM for their significance in an independent sample cohort. A minimal set of 35 peptides mapping to 33 proteins, were modeled to segregate different injury groups (AUC =93% for AR, 99% for CAN, 83% for BKVN). Urinary proteome discovery and targeted validation identified urine protein fingerprints for non-invasive differentiation of kidney transplant injuries, thus opening the door for personalized immune risk assessment and therapy.

Environmental Molecular Sciences Laboratory↗
DOE OSTI2026

Circadian immunometabolic states impart a temporal response to SARS-CoV-2 spike proteins in mammalian macrophages

Circadian rhythms, the 24-hour cycles that tune organismal physiology to the daily rhythms of light and dark, optimally organize cellular processes such as metabolism and mitochondrial function. In mammals, macrophage functions are regulated by these 24-hour circadian rhythms such that the immunometabolic response is coordinated across the day, consolidating macrophage physiology into temporally distinct phases to time the cellular immune response. However, while it is known that there are time-of-day specific responses to stress in a macrophage, little has been done to determine if circadian regulation coordinates the response of a macrophage to real-world pathogens. Importantly, key proteins in the response to viral infection have been found to be under circadian control, and time of day of application is known to affect the efficacy of vaccinations, including in the case of the COVID-19 virus. Therefore, to investigate if the circadian regulation of macrophage physiology imparted a time-of-day response to viral exposure, we exposed primary mouse and human macrophages to the SARS-CoV-1 and CoV-2 spike proteins at different times over the circadian day. To establish a time-of-day effect, we performed a multi-omics analysis and in vitro tissue culture assays examining macrophage responses over circadian time. We found that, conserved across the species, the timing of spike protein exposure dictated two distinct temporal responses which were characterized by hallmarks of immunometabolic suppression and modest inflammatory activation. However, these responses were primarily influenced by central metabolic and mitochondrial changes and not by classical immune activation.

Circadian Biology↗
DOE OSTI2022

Extracellular vesicles in β cell biology: Role of lipids in vesicle biogenesis, cargo, and intercellular signaling

Background: Type 1 diabetes (T1D) is a complex autoimmune disorder whose pathogenesis involves an intricate interplay between ß cells of the pancreatic islet, other islet cells, and cells of the immune system. Direct intercellular communication within the islet occurs via cell surface proteins and indirect intercellular communication has traditionally been as occurring via secreted proteins (e.g., endocrine hormones and cytokines). However, recent literature suggests that extracellular vesicles (EVs) secreted by ß cells constitute an additional and biologically important mechanism for transmitting signals to adjacent ß cells or immune cells. Scope of Review: This review summarizes the general mechanisms of EV formation, with a particular focus on how lipids and lipid signaling pathways influence their formation and cargo. We review the implications of EV release from ß cells for T1D pathogenesis, how EVs and their cargo might be leveraged as biomarkers of the early events leading to T1D, and how EVs might be engineered as a therapeutic candidate to counter T1D outcomes. Major Conclusions: Islet ß cells have been viewed as initiators and propagators of the cellular circuit giving rise to autoimmunity in T1D. In this context, emerging literature suggests that EVs may represent a conduit for communication that holds more comprehensive messaging about the ß cells from which they arise. As the field of EV biology advances, it opens the possibility that intervening with EV formation and cargo loading could be a novel disease-modifying approach in T1D.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗