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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Gut microbiota and its therapeutic implications in tumor microenvironment interactions

The development of cancer is not just the growth and proliferation of a single transformed cell, but its tumor microenvironment (TME) also coevolves with it, which is primarily involved in tumor initiation, development, metastasis, and therapeutic responses. Recent years, TME has been emerged as a potential target for cancer diagnosis and treatment. However, the clinical efficacy of treatments targeting the TME, especially its specific components, remains insufficient. In parallel, the gut microbiome is an essential TME component that is crucial in cancer immunotherapy. Thus, assessing and constructing frameworks between the gut microbiota and the TME can significantly enhance the exploration of effective treatment strategies for various tumors. In this review the role of the gut microbiota in human cancers, including its function and relationship with various tumors was summarized. In addition, the interaction between the gut microbiota and the TME as well as its potential applications in cancer therapeutics was described. Furthermore, it was summarized that fecal microbiota transplantation, dietary adjustments, and synthetic biology to introduce gut microbiota-based medical technologies for cancer treatment. This review provides a comprehensive summary for uncovering the mechanism underlying the effects of the gut microbiota on the TME and lays a foundation for the development of personalized medicine in further studies.

Feng, Pengya↗
DOE OSTI2022

Gantry-Based 5-Fraction Elective Nodal Irradiation in Unfavorable-Risk Prostate Cancer: Outcomes From 2 Prospective Studies Comparing SABR Boost With MR Dose-Painted HDR Brachytherapy Boost

Guidelines from the American Society of Clinical Oncology and Cancer Care Ontario recommend brachytherapy boost for patients with intermediate-risk or high-risk prostate cancer. SABR is an emerging technique for prostate cancer, but its use in high-risk disease is limited. Efficacy, toxic effects, and quality of life (QoL) were compared in patients treated on 2 prospective protocols that used SABR boost or magnetic resonance–guided high-dose-rate brachytherapy (HDR-BT) boost with 6 to 18 months of androgen deprivation therapy (ADT).

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

A reference tissue atlas for the human kidney

Kidney Precision Medicine Project (KPMP) is building a spatially specified human kidney tissue atlas in health and disease with single-cell resolution. Here, we describe the construction of an integrated reference map of cells, pathways, and genes using unaffected regions of nephrectomy tissues and undiseased human biopsies from 56 adult subjects. We use single-cell/nucleus transcriptomics, subsegmental laser microdissection transcriptomics and proteomics, near-single-cell proteomics, 3D and CODEX imaging, and spatial metabolomics to hierarchically identify genes, pathways, and cells. Integrated data from these different technologies coherently identify cell types/subtypes within different nephron segments and the interstitium. These profiles describe cell-level functional organization of the kidney following its physiological functions and link cell subtypes to genes, proteins, metabolites, and pathways. They further show that messenger RNA levels along the nephron are congruent with the subsegmental physiological activity. This reference atlas provides a framework for the classification of kidney disease when multiple molecular mechanisms underlie convergent clinical phenotypes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

The application of cinematic rendering to CT evaluation of upper tract urothelial tumors: principles and practice

Upper tract urothelial carcinoma (UTUC) is a relatively uncommon but aggressive genitourinary malignancy for which multi-phase contrast-enhanced computed tomography (CT) plays an important role in evaluation and staging. 3D imaging with maximum intensity projection (MIP) and volume-rendered (VR) images has been described as a useful means of evaluating UTUC. In this study, we describe the technique of a novel 3D methodology known as cinematic rendering (CR) and provide clinical examples of UTUC visualized with CR. CR utilizes a complex universal lighting model in order to create photorealistic images with improved detail and depth in comparison to MIP or VR images. In the case of UTUC, CR can be used in different contrast phases to show abnormally thickened and enhancing urothelium or filling defects in the renal collecting system or ureters in the excretory phase. CR images can also be manipulated in order to generate translucent views of the upper urinary tract in order to add conspicuity to intraluminal findings.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2024

Crimean Congo hemorrhagic fever virus nucleoprotein and GP38 subunit vaccine combination prevents morbidity in mice

Immunizing mice with Crimean-Congo hemorrhagic fever virus (CCHFV) nucleoprotein (NP), glycoprotein precursor (GPC), or with the GP38 domain of GPC, can be protective when the proteins are delivered with viral vectors or as a DNA or RNA vaccine. Subunit vaccines are a safe and cost-effective alternative to some vaccine platforms, but Gc and Gn glycoprotein subunit vaccines for CCHFV fail to protect despite eliciting high levels of neutralizing antibodies. Here, we investigated humoral and cellular immune responses and the protective efficacy of recombinant NP, GP38, and GP38 forms (GP85 and GP160) associated with the highly glycosylated mucin-like (MLD) domain, as well as the NP + GP38 combination. Vaccination with GP160, GP85, or GP38 did not confer protection, and vaccination with the MLD-associated GP38 forms blunted the humoral immune responses to GP38, worsened clinical chemistry, and increased viral RNA in the blood compared to the GP38 vaccination. In contrast, NP vaccination conferred 100% protection from lethal outcome and was associated with mild clinical disease, while the NP + GP38 combination conferred even more robust protection by reducing morbidity compared to mice receiving NP alone. Thus, recombinant CCHFV NP alone is a promising vaccine candidate conferring 100% survival against heterologous challenge. Moreover, incorporation of GP38 should be considered as it further enhances subunit vaccine efficacy by reducing morbidity in surviving animals.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

67 Cu Production Capabilities: A Mini Review

Is the 67 Cu production worldwide feasible for expanding preclinical and clinical studies? How can we face the ingrowing demands of this emerging and promising theranostic radionuclide for personalized therapies? This review looks at the different production routes, including the accelerator- and reactor-based ones, providing a comprehensive overview of the actual 67 Cu supply, with brief insight into its use in non-clinical and clinical studies. In addition to the most often explored nuclear reactions, this work focuses on the 67 Cu separation and purification techniques, as well as the target material recovery procedures that are mandatory for the economic sustainability of the production cycle. The quality aspects, such as radiochemical, chemical, and radionuclidic purity, with particular attention to the coproduction of the counterpart 64 Cu, are also taken into account, with detailed comparisons among the different production routes. Future possibilities related to new infrastructures are included in this work, as well as new developments on the radiopharmaceuticals aspects.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2020

Predicting antimicrobial susceptibility from the bacterial genome: A new paradigm for one health resistance monitoring

The laboratory identification of antibacterial resistance is a cornerstone of infectious disease medicine. In vitro antimicrobial susceptibility testing has long been based on the growth response of organisms in pure culture to a defined concentration of antimicrobial agents. By comparing individual isolates to wild type susceptibility patterns, strains with acquired resistance can be identified. Acquired resistance can also be detected genetically. After many decades of research, the inventory of genes underlying antimicrobial resistance (AMR) is well known for several pathogenic genera including zoonotic enteric organisms such as Salmonella and Campylobacter and continues to grow substantially for others. With the decline in costs for large scale DNA sequencing, it is now practicable to characterize bacteria using whole genome sequencing (WGS), including the carriage of resistance genes in individual microorganisms and those present in complex biological samples. With genomics we can generate comprehensive, detailed information on the bacterium, the mechanisms of antibiotic resistance, clues to its source, and the nature of mobile DNA elements by which resistance spreads. These developments point to a new paradigm for antimicrobial resistance detection and tracking for both clinical and public health purposes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)

Polymerase eta (or Pol η or POLH) is a specialized DNA polymerase that is able to bypass certain blocking lesions, such as those generated by ultraviolet radiation (UVR) or cisplatin, and is deployed to replication foci for translesion synthesis as part of the DNA damage response (DDR). Inherited defects in the gene encoding POLH (a.k.a., XPV) are associated with the rare, sun-sensitive, cancer-prone disorder, xeroderma pigmentosum, owing to the enzyme’s ability to accurately bypass UVR-induced thymine dimers. In standard-of-care cancer therapies involving platinum-based clinical agents, e.g., cisplatin or oxaliplatin, POLH can bypass platinum-DNA adducts, negating benefits of the treatment and enabling drug resistance. POLH inhibition can sensitize cells to platinum-based chemotherapies, and the polymerase has also been implicated in resistance to nucleoside analogs, such as gemcitabine. POLH overexpression has been linked to the development of chemoresistance in several cancers, including lung, ovarian, and bladder. Co-inhibition of POLH and the ATR serine/threonine kinase, another DDR protein, causes synthetic lethality in a range of cancers, reinforcing that POLH is an emerging target for the development of novel oncology therapeutics. Using a fragment-based drug discovery approach in combination with an optimized crystallization screen, we have solved the first X-ray crystal structures of small novel drug-like compounds, i.e., fragments, bound to POLH, as starting points for the design of POLH inhibitors. The intrinsic molecular resolution afforded by the method can be quickly exploited in fragment growth and elaboration as well as analog scoping and scaffold hopping using medicinal and computational chemistry to advance hits to lead. An initial small round of medicinal chemistry has resulted in inhibitors with a range of functional activity in an in vitro biochemical assay, leading to the rapid identification of an inhibitor to advance to subsequent rounds of chemistry to generate a lead compound. Importantly, our chemical matter is different from the traditional nucleoside analog-based approaches for targeting DNA polymerases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Production of Radiohalogens: Bromine and Astatine for Imaging and Therapy

Objective: This collaborative proposal between the University of Alabama at Birmingham (UAB), University of Wisconsin, Madison (UWisc) and the University of Pennsylvania (Penn) aims to research the efficient production of high purity, clinical grade radiohalogens for preclinical and translational applications by optimizing the cyclotron targetry and separation chemistry of 76,77Br and 211At for use in imaging and therapy. Proposed Research and Methods: During the course of this project, faculty and trainees at our three institutions will use the complementary infrastructure available to examine the 76Se(p,n)76Br, 77Se(p,n)77Br, 78Se(p,2n)77Br, natAs(α,2n)77Br ,80Kr(p,α)77Br and 209Bi(α, 2n)211At reactions as routes to the production of these valuable radiohalogens for imaging and therapy. Working together we aim to optimize both solid and gas targetry, including reclamation of expensive enriched material. We will develop high yielding recovery processes based on dry distillation and ion exchange techniques. We will also create a comprehensive set of quality control procedures to ensure we are producing our radioisotopes in the highest radiochemical and chemical purity possible. By bringing three institutions together to perform research and development we provide the unique opportunity to build an everlasting cooperative culture in the field of nuclear medicine research by enabling academic centers to delve into the fields of radiohalogen chemistry. In addition, each institution involved holds different skills and expertise and a collaborative grant will facilitate the cross-pollination of ideas, techniques, and build strong bonds that unite under the DOE mission. Additionally, our work does not stop at the completion of this proposal, rather this proposal allows us to gain the momentum needed to get our research and developmental efforts off the ground thereby creating a network of three institutions dedicated to the advancement of isotope production for medical research.

07 ISOTOPE AND RADIATION SOURCES↗
DOE OSTI2020

A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors**

The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2M Pro ) to digest two of its translated long polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replicating in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1M Pro ), we have designed and synthesized a series of SC2M Pro inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2M Pro active-site cysteine C145. All inhibitors display high potency with K i values at or below 100 nM. The most potent compound, MPI3, has as a K i value of 8.3 nM. Crystallographic analyses of SC2M Pro bound to seven inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549/ACE2 cells. Two inhibitors, MPI5 and MPI8, completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5-5 μM and A549/ACE2 cells at 0.16-0.31 μM. Their virus inhibition potency is much higher than that of some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2M Pro inhibitors with ultra-high antiviral potency.

3C-like protease↗
DOE OSTI2022

Logistic Regression in Clinical Studies

• A logistic regression model is used when the outcome of interest is binary. The term “logistic” refers to the underlying “logit” (log odds) function that is used to model the binary outcome. • Odds ratios are produced from a logistic regression model and have a useful interpretation. • Tips, tricks and concepts used to fit logistic regression models are similar to those used in linear regression models. • Modeling building that is knowledge-based rather than automatic is preferred in most applications of logistic regression. • A logistic regression model that is overparameterized (ie, too many variables for too few events) can result in odds ratios that are implausibly large and confidence intervals that are wide and uninterpretable. These types of “overfitted” models should be avoided. • Logistic regression models can be fit using most standard statistical software.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2020

Small animal PET: a review of what we have done and where we are going

Abstract Small animal research is an essential tool in studying both pharmaceutical biodistribution and disease progression over time. Furthermore, through the rapid development of in vivo imaging technology over the last few decades, small animal imaging (also referred to as preclinical imaging) has become a mainstay for all fields of biologic research and a center point for most preclinical cancer research. Preclinical imaging modalities include optical, MRI and MRS, microCT, small animal PET, ultrasound, and photoacoustic, each with their individual strengths. The strong points of small animal PET are its translatability to the clinic; its quantitative imaging capabilities; its whole-body imaging ability to dynamically trace functional/biochemical processes; its ability to provide useful images with only nano- to pico- molar concentrations of administered compounds; and its ability to study animals serially over time. This review paper gives an overview of the development and evolution of small animal PET imaging. It provides an overview of detector designs; system configurations; multimodality PET imaging systems; image reconstruction and analysis tools; and an overview of research and commercially available small animal PET systems. It concludes with a look toward developing technologies/methodologies that will further enhance the impact of small animal PET imaging on medical research in the future.

Engineering↗
DOE OSTI2025

Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex

Cancer cells are acutely dependent on nuclear transport due to elevated transcriptional activity, suggesting an unrealized opportunity for selective therapeutic inhibition of the nuclear pore complex (NPC). Through large-scale phenotypic profiling of cancer cell lines, genome-scale functional genomic modifier screens, and mass spectrometry–based proteomics, we discovered that the clinical drug PRLX-93936 is a molecular glue that binds and reprograms the TRIM21 ubiquitin ligase to degrade the NPC. Upon compound-induced TRIM21 recruitment, the nuclear pore is ubiquitylated and degraded, resulting in the loss of short-lived cytoplasmic mRNA transcripts and the induction of cancer cell apoptosis. Direct compound binding to TRIM21 was confirmed via surface plasmon resonance and X-ray crystallography, whereas compound-induced TRIM21–nucleoporin complex formation was demonstrated through multiple orthogonal approaches in cells and in vitro. Phenotype-guided optimization yielded compounds with 10-fold greater potency and drug-like properties, along with robust pharmacokinetics and efficacy against pancreatic cancer xenografts and patient-derived organoids.

Yuan, Linjie [Stanford School of Medicine, CA (Uni↗
DOE OSTI2023

Inclusion of Biological Targets in the Analysis of Electrical Characteristics of Non-Thermal Plasma Discharge

In Plasma Medicine studies, the effect of non-thermal plasma (NTP) on biological targets is typically correlated with the amount of stable reactive oxygen and nitrogen species produced in a liquid medium. The effect of NTP and the response of the biological target on cellular redox mechanisms is overlooked in these investigations. Additionally, the influence of electrical properties of cells on the physical properties of NTP is neglected. Therefore, we used a floating electrode dielectric barrier discharge plasma to explore the impact of cell structure, size, and viability of the biological target on the physical properties of NTP. Lissajous figures were used to determine circuit capacitance and energy per cycle during NTP exposure of different cell suspensions. We show that both, structural integrity and active enzymic processes of cells change the electrical properties of NTP. Correlations were also drawn between NTP-produced hydrogen peroxide and nitrite with measured capacitance. Our studies indicate that the observed changes between different cell suspensions may be due to a feedback loop between the biological target and the NTP source. In future studies, a more detailed analysis is needed to improve the control of clinical NTP devices.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2020

A spot test for determination of residual TBA levels in 18 F-radiotracers for human use using Dragendorff reagent

When utilizing [ 18 F]tetrabutylammonium fluoride ([ 18 F]TBAF) in the synthesis of 18 F-labeled radiotracers for clinical positron emission tomography (PET) imaging, it is necessary to confirm that residual TBA levels in formulated doses do not exceed established specifications (≤2.6 mg per patient dose). Historically this has been accomplished using HPLC, but this is time consuming for short-lived PET radiotracers and limited by the need for expensive equipment. This motivated us to introduce a TLC spot test for determining residual TBA, and we have developed a new method which employs the Dragendorff reagent. Herein we report details of the TLC method and use it to quantify residual TBA in different formulations of 6-[ 18 F]fluoro-DOPA.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

A Primer on Dose-Response Data Modeling in Radiation Therapy

An overview of common approaches used to assess a dose response for radiation therapy–associated endpoints is presented, using lung toxicity data sets analyzed as a part of the High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic effort as an example. Each component presented (eg, data-driven analysis, dose-response analysis, and calculating uncertainties on model prediction) is addressed using established approaches. Specifically, the maximum likelihood method was used to calculate best parameter values of the commonly used logistic model, the profile-likelihood to calculate confidence intervals on model parameters, and the likelihood ratio to determine whether the observed data fit is statistically significant. The bootstrap method was used to calculate confidence intervals for model predictions. Correlated behavior of model parameters and implication for interpreting dose response are discussed.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Superiority of compensatory reserve measurement compared with the Shock index for early and accurate detection of reduced central blood volume status

Shock index (SI) equals the ratio of heart rate (HR) to systolic blood pressure (SBP) with clinical evidence that it is more sensitive for trauma patient status assessment and prediction of outcome compared with either HR or SBP alone. We used lower body negative pressure (LBNP) as a human model of central hypovolemia and compensatory reserve measurement (CRM) validated for accurate tracking of reduced central blood volume to test the hypotheses that SI: (1) presents a late signal of central blood volume status; (2) displays poor sensitivity and specificity for predicting the onset of hemodynamic decompensation; and (3) cannot identify individuals at greatest risk for the onset of circulatory shock. We measured HR, SBP, and CRM in 172 human subjects (19–55 years) during progressive LBNP designed to determine tolerance to central hypovolemia as a model of hemorrhage. Subjects were subsequently divided into those with high tolerance (HT) (n = 118) and low tolerance (LT) (n = 54) based on completion of 60 mm Hg LBNP. The time course relationship between SI and CRM was determined and receiver operating characteristic (ROC) area under the curve (AUC) was calculated for sensitivity and specificity of CRM and SI to predict hemodynamic decompensation using clinically defined thresholds of 40% for CRM and 0.9 for SI. The time and level of LBNP required to reach a SI = 0.9 (~60 mm Hg LBNP) was significantly greater (p < 0.001) compared with CRM that reached 40% at ~40 mm Hg LBNP. Shock index did not differ between HT and LT subjects at 45 mm Hg LBNP levels. ROC AUC for CRM was 0.95 (95% CI = 0.94–0.97) compared with 0.91 (0.89–0.94) for SI (p = 0.0002). Despite high sensitivity and specificity, SI delays time to detect reductions in central blood volume with failure to distinguish individuals with varying tolerances to central hypovolemia.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Chronic Cardiotoxicity Assays Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs)

Cardiomyocytes (CMs) differentiated from human induced pluripotent stem cells (hiPSCs) are increasingly used in cardiac safety assessment, disease modeling and regenerative medicine. A vast majority of cardiotoxicity studies in the past have tested acute effects of compounds and drugs; however, these studies lack information on the morphological or physiological responses that may occur after prolonged exposure to a cardiotoxic compound. In this review, we focus on recent advances in chronic cardiotoxicity assays using hiPSC-CMs. We summarize recently published literature on hiPSC-CMs assays applied to chronic cardiotoxicity induced by anticancer agents, as well as non-cancer classes of drugs, including antibiotics, anti-hepatitis C virus (HCV) and antidiabetic drugs. We then review publications on the implementation of hiPSC-CMs-based assays to investigate the effects of non-pharmaceutical cardiotoxicants, such as environmental chemicals or chronic alcohol consumption. We also highlight studies demonstrating the chronic effects of smoking and implementation of hiPSC-CMs to perform genomic screens and metabolomics-based biomarker assay development. The acceptance and wide implementation of hiPSC-CMs-based assays for chronic cardiotoxicity assessment will require multi-site standardization of assay protocols, chronic cardiac maturity marker reproducibility, time points optimization, minimal cellular variation (commercial vs. lab reprogrammed), stringent and matched controls and close clinical setting resemblance. A comprehensive investigation of long-term repeated exposure-induced effects on both the structure and function of cardiomyocytes can provide mechanistic insights and recapitulate drug and environmental cardiotoxicity.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗