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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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At least 127 records · Page 7
All sourcesNASA NTRSDOE OSTI
NASA NTRS2002

Enhanced animal growth via ligand-regulated GHRH myogenic-injectable vectors

Regulated animal growth occurred following a single electroporated injection of a mixture of two plasmids (10 microg of DNA), one expressing the GeneSwitch regulator protein, the other an inducible growth hormone releasing hormone (GHRH) gene, into the tibialis anterior muscles of adult SCID mice. Administration of the ligand mifepristone (MFP) up-regulated GHRH expression, as shown by elevations of IGF-I levels, and when MFP dosing was withdrawn, IGF-I returned to baseline levels. Five cycles of IGF-I induction were observed during a five-month period. Chronic MFP dosing for 25 days increased lean body mass, weight gain, and bone mineral density significantly compared with non-MFP treated controls. In summary, long-term drug-regulated GHRH expression was achieved following plasmid-based gene therapy, and chronic induction of GHRH expression in adult animals led to improvements in weight gain and body composition.

NASA Discipline Musculoskeletal↗
DOE OSTI2023

Microelectrode Arrays Measure Blocking of Voltage-Gated Calcium Ion Channels on Supported Lipid Bilayers Derived from Primary Neurons

Drug studies targeting neuronal ion channels are crucial to understand neuronal function and develop therapies for neurological diseases. The traditional method to study neuronal ion-channel activities heavily relies on the whole-cell patch clamp as the industry standard. However, this technique is both technically challenging and labour-intensive, while involving the complexity of keeping cells alive with low throughput. Therefore, the shortcomings are limiting the efficiency of ion-channel-related neuroscience research and drug testing. Here, this work reports a new system of integrating neuron membranes with organic microelectrode arrays (OMEAs) for ion-channel-related drug studies. This work demonstrates that the supported lipid bilayers (SLBs) derived from both neuron-like (neuroblastoma) cells and primary neurons are integrated with OMEAs for the first time. The increased expression of voltage-gated calcium (CaV) ion channels on differentiated SH-SY5Y SLBs compared to non-differentiated ones is sensed electrically. Also, dose-response of the CaV ion-channel blocking effect on primary cortical neuronal SLBs from rats is monitored. The dose range causing ion channel blocking is comparable to literature. This system overcomes the major challenges from traditional methods (e.g., patch clamp) and showcases an easy-to-test, rapid, ultra-sensitive, cell-free, and high-throughput platform to monitor dose-dependent ion-channel blocking effects on native neuronal membranes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

177 Lu and 227 Th Labeled 3,4,3-(LI-1,2-HOPO): characterization, optimized synthesis, biological distribution and dosimetry

Objectives: Interest in targeted radionuclide therapy has greatly increased namely due to the FDA approval of radiotherapeutic drugs such as Lutathera The identification of chelators that can bind diag- nostic and therapeutic radionuclides would allow facile development of agents tailored for personalized medicine. Hydroxypyridinonate (HOPO) derivatives have been demonstrated as effective decorpo- ration agents for actinides owing to their hard oxygen donor atoms and strong complexation. Utilizing these molecules as chelators for potential nuclear medicine agents should allow for radiometals to be effectively sequestered by the ligand. The aim of this work was to evaluate the in vivo stability of 3-4-3-(LI-1,2-HOPO) (HOPO for short) with 177 Lu and 227 Th as potential beta- and alpha-emitting radiothera- peutic complexes, respectively.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

Gestational exposure to HIV drugs alters intestinal mucosa-associated microbial diversity in adult rat offspring

The antiretroviral (ARV) drug combination of abacavir sulfate, dolutegravir, and lamivudine [ABC/DTG/3TC; Tri combination Anti-retroviral therapy (TC-ART)] has revolutionized HIV treatment by effectively targeting different stages of viral replication. Despite its therapeutic efficiency for maintaining low viremia in the mother during pregnancy, there are concerns for long-term liabilities in offspring that are indirectly exposed during vulnerable periods of development. The commensal microbiota plays a crucial role in maintaining overall gut health, and disruption of the microbiome is often linked to various extraintestinal effects such as immune dysregulation and inflammation. We recently reported the effects of this drug combination in altering fecal microbiome composition of aged rats perinatally exposed to ABC/DTG/3TC-ART. The fecal microbiome can provide only a snapshot of the composition of microbial community at the end of the digestive tract, which may not reflect the microbial population interacting with ileal mucosa. Thus, the current work reports the effects of this drug combination in the gut mucosa-associated microbiome of the same animals, which showed significant microbial diversity and species richness in high dose exposed female adult offspring, along with dose-dependent changes in Firmicutes/Bacteroidetes ratio. The high dose exposure also showed an increase in opportunistic bacterial species in male animals. Overall, we found that, similar to the fecal microbiome, perinatal exposure to TC-ART led to sex- and dose-dependent alterations in the gut mucosa-associated microbial population in aged rats, suggesting that early life exposure to these drugs may influence gut mucosa-associated immune responses and intestinal permeability.

Research & Experimental Medicine↗
DOE OSTI2022

Development and validation of a quantitative proton NMR method for the analysis of pregnenolone

Pregnenolone (PREG) is an endogenous steroid frequently sold as an over-the-counter dietary supplement touted to promote neurological and immunological health. While the PREG dietary supplement is added to the diet for health benefits, there are no FDA approved PREG drugs. However, compounded PREG drug products are available to U.S. patients. The FDA works with state regulatory authorities on the oversight of compounding activities, including developing 503A and 503B lists of bulk substances that compounders are permitted to use. PREG is one of the substances publicly nominated to be included on the 503B list. Compounded hormone therapies such as those using PREG are of interest given the lack of standardization in compounded drug products which may increase the possibility of underdosing, overdosing, or contamination. However, no USP monograph currently exists to evaluate the quality of PREG drug substance or product. To address knowledge gaps and assist in quality control, a simple and rapid quantitative proton nuclear magnetic resonance spectroscopy (qNMR) method for the identification and assay of PREG in different types of PREG products was developed and validated. PREG samples were characterized using 1D 1 H and 2D 1 H– 13 C HSQC NMR spectra. The qNMR assay method (taking approximately 10 min per NMR spectrum) was validated for precision, accuracy, specificity, robustness and linearity per ICH Q2(R1) guidance. The method was validated in a range from 0.032 to 3.2 mg/mL. As a proof of concept, seven PREG bulk substance samples, three tablet and two capsule PREG dietary supplements were assessed by the qNMR analytical procedure. NMR data from all tested samples met the expected criteria for identification and assay. The results demonstrate the potential of qNMR for the quality assessment of different types of PREG samples.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Elucidating molecular interactions of L-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance

Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (-)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (-)-FTC-TP and (-)-3TC-TP and drug resistance by M184V. (-)-FTC-TP and (-)-3TC-TP have higher binding affinities (1/K d 200-fold) K d for the L-nucleotides and moderately higher (>9-fold) K d for the D-isomers compared to dCTP. The M184V RT structure illustrates how the mutation repositions the oxathiolane of (-)-FTC-TP and shifts its triphosphate into a non-productive conformation.

Life Sciences & Biomedicine - Other Topics↗
DOE OSTI2021

Integrin α5 mediates intrinsic cisplatin resistance in three-dimensional nasopharyngeal carcinoma spheroids via the inhibition of phosphorylated ERK /caspase-3 induced apoptosis

Highlights: • Highly expressed integrin α5 was observed in in vitro three-dimensional NPC spheroids. • The overexpression of integrin α5 in NPC spheroids demonstrated a correlation with intrinsic cisplatin resistance. • The integrin α5-induced intrinsic cisplatin resistance was mediated by an inactivation of ERK/caspase-3-induced apoptosis. • ATN-161, an integrin α5β1 inhibitor, reduced integrin α5 expression and increased sensitization to cisplatin in NPC spheroids. • ATN-161 reversed the intrinsic cisplatin resistance in NPC spheroids by reactivating ERK/caspase-3-induced apoptosis. Nasopharyngeal carcinoma (NPC) originates in the nasopharynx epithelium. Although concurrent chemoradiation therapy followed by chemotherapy is considered as an effective treatment, there is substantial drug resistance in locally advanced NPC patients. One major contributor to the chemoresistance includes aberrant expression of cell adhesion molecules, such as integrin α and β subunits, giving rise to cell adhesion-mediated drug resistance. Thus, the aim of this study was to investigate the effect of integrin α5 on the development of intrinsic cisplatin resistance in NPC and the associated underlying mechanisms using in vitro three-dimensional (3D) spheroid models, as well as induced cisplatin-resistant NPC (NPCcisR). We demonstrated that established 3D highly- (5-8F) and lowly- (6-10B) metastatic NPC spheroids overexpressed integrin α5 and aggravated their resistance to cisplatin. Besides, enhanced integrin α5 resulted in substantially reduced growth, corresponding to G{sub 0}/G{sub 1} and G{sub 2}/M cell cycle arrest. In addition, 5-8FcisR and 6-10BcisR cells in 3D forms synergistically strengthened endurance of their spheroids to cisplatin treatment as observed by increased resistance index (RI) and decreased apoptosis. Mechanistically, the aberrantly expressed integrin α5 decreased drug susceptibility in NPC spheroids by inactivating ERK and inhibition of caspase-3 inducing apoptosis. Furthermore, the effect of integrin α5 inducing intrinsic resistance was verified via treatment with ATN-161, a peptide inhibitor for integrin α5β1. The results showed dramatic reduction in integrin α5 expression, reversal of ERK phosphorylation and caspase-3 cleavage, together with elevated cisplatin sensitivity, indicating regulation of innate drug resistance via integrin α5. Taken together, our findings suggest that integrin α5 could act as a promising target to enhance the chemotherapeutic sensitivity in NPC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Human cytochrome P450 17A1 structures with metabolites of prostate cancer drug abiraterone reveal substrate-binding plasticity and a second binding site

Abiraterone acetate is a first-line therapy for castration-resistant prostate cancer. This prodrug is deacetylated in vivo to abiraterone, which is a potent and specific inhibitor of cytochrome P450 17A1 (CYP17A1). CYP17A1 performs two sequential steps that are required for the biosynthesis of androgens that drive prostate cancer proliferation, analogous to estrogens in breast cancer. Abiraterone can be further metabolized in vivo on the steroid A ring to multiple metabolites that also inhibit CYP17A1. Despite its design as an active-site-directed substrate analog, abiraterone and its metabolites demonstrate mixed competitive/noncompetitive inhibition. To understand their binding, we solved the X-ray structures of CYP17A1 with three primary abiraterone metabolites. Despite different conformations of the steroid A ring and substituents, all three bound in the CYP17A1 active site with the steroid core packed against the I helix and the A ring C3 keto or hydroxyl oxygen forming a hydrogen bond with N202 similar to abiraterone itself. The structure of CYP17A1 with 3-keto, 5α-abiraterone was solved to 2.0 Å, the highest resolution to date for a CYP17A1 complex. This structure had additional electron density near the F/G loop, which is likely a second molecule of the inhibitor and which may explain the noncompetitive inhibition. Mutation of the adjacent Asn52 to Tyr positions its side chain in this space, maintains enzyme activity, and prevents binding of the peripheral ligand. Collectively, our findings provide further insight into abiraterone metabolite binding and CYP17A1 function.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Dexamethasone reduces the formation of thoracic aortic aneurysm and dissection in a murine model

Highlights: • Dexamethasone attenuated thoracic aortic aneurysm and dissection in a mouse model. • Dexamethasone reduced infiltration of inflammatory cell and apoptosis of vascular smooth muscle cell and fibroblast. • Dexamethasone partly alleviated degradation of collagen and phenotype switch. • DEX might ameliorate thoracic aortic aneurysm and dissection by suppressing NF-κB signaling pathway. Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease with no effective pharmaceutical therapies currently available. Inflammation plays a key role in the progression of aneurysms. Dexamethasone (DEX), a synthetic glucocorticoid, has showed alleviating effects on cells in vitro from TAAD patients. Here we performed a study aiming at investigating the protective role of DEX in a β-aminopropionitrile monofumarate (BAPN)-induced TAAD mouse model. DEX (dose: 0.04 mg/kg/day) treatment significantly reduced the aortic diameter and inhibited TAAD formation. DEX reduced infiltration of macrophages and neutrophils, apoptosis of vascular smooth muscle cells (VSMCs), expression of metalloproteinase 2/9, and extracellular matrix degradation in BAPN-treated TAAD mice. Furthermore, DEX therapy downregulated the expression of p-p65 in macrophages and VSMCs, which suggested that DEX might ameliorate BAPN-induced TAAD by suppressing NF-κB signaling. Therefore, DEX therapy attenuates the progression of BAPN-induced TAAD murine model and could be used as an effective adjuvant therapy for treating TAAD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Structure-guided design of pure orthosteric inhibitors of αIIbβ3 that prevent thrombosis but preserve hemostasis

A prevailing dogma is that inhibition of vascular thrombosis by antagonizing platelet integrin αIIbβ3 cannot be achieved without compromising hemostasis, thus causing serious bleeding and increased morbidity and mortality. It is speculated that these adverse outcomes result from drug-induced activating conformational changes in αIIbβ3 but direct proof is lacking. Here, we report the structure-guided design of peptide Hr10 and a modified form of the partial agonist drug tirofiban that act as “pure” antagonists of αIIbβ3, i.e., they no longer induce the conformational changes in αIIbβ3. Both agents inhibit human platelet aggregation but preserve clot retraction. Hr10 and modified tirofiban are as effective as partial agonist drugs in inhibiting vascular thrombosis in humanized mice, but neither causes serious bleeding, establishing a causal link between partial agonism and impaired hemostasis. Pure orthosteric inhibitors of αIIbβ3 may thus provide safer alternatives for human therapy, and valuable tools to probe structure–activity relationships in integrins.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Translation of DNA Damage Response Inhibitors as Chemoradiation Sensitizers From the Laboratory to the Clinic

Combination therapies with agents targeting the DNA damage response (DDR) offer an opportunity to selectively enhance the therapeutic index of chemoradiation or eliminate use of chemotherapy altogether. The successful translation of DDR inhibitors to clinical use requires investigating both their direct actions as (chemo)radiosensitizers and their potential to stimulate tumor immunogenicity. Beginning with high-throughput screening using both viability and DNA damage-reporter assays, followed by validation in gold-standard radiation colony-forming assays and in vitro assessment of mechanistic effects on the DDR, we describe proven strategies and methods leading to the clinical development of DDR inhibitors both with radiation alone and in combination with chemoradiation. Beyond these in vitro studies, we discuss the impact of key features of human xenograft and syngeneic mouse models on the relevance of in vivo tumor efficacy studies, particularly with regard to the immunogenic effects of combined therapy with radiation and DDR inhibitors. Finally, we describe recent technological advances in radiation delivery (using the small animal radiation research platform) that allow for conformal, clinically relevant radiation therapy in mouse models. This overall approach is critical to the successful clinical development and ultimate Food and Drug Administration approval of DDR inhibitors as (chemo)radiation sensitizers.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

Dual function of Candida auris mannosyltransferase, MNT5, in biofilm community protection from antifungal therapy and the host

Screen of mutants from a mannosyltransferase family identified the importance of MNT5 for C. auris biofilm drug resistance and neutrophil evasion. Biochemical analysis of the mnt5∆ mutant matrix and cell wall identified alterations in the mannan structures. Resistance and matrix for mnt5∆ were restored with delivery of wild-type matrix via extracellular vesicles. Analysis of the mnt5∆ cell wall revealed a reduction in mannan and compensatory increase in cell surface glucan and chitin, suggesting a role for MNT5 in mannan masking of pathogen-associated molecular patterns.

Candida auris↗
DOE OSTI2022

Development of radiopharmaceuticals for targeted alpha therapy: Where do we stand?

Targeted alpha therapy is an oncological treatment, where cytotoxic doses of alpha radiation are locally delivered to tumor cells, while the surrounding healthy tissue is minimally affected. This therapeutic strategy relies on radiopharmaceuticals made of medically relevant radionuclides chelated by ligands, and conjugated to targeting vectors, which promote the drug accumulation in tumor sites. This review discusses the state-of-the-art in the development of radiopharmaceuticals for targeted alpha therapy, breaking down their key structural components, such as radioisotope, targeting vector, and delivery formulation, and analyzing their pros and cons. Moreover, we discuss current drawbacks that are holding back targeted alpha therapy in the clinic, and identify ongoing strategies in field to overcome those issues, including radioisotope encapsulation in nanoformulations to prevent the release of the daughters. Lastly, we critically discuss potential opportunities the field holds, which may contribute to targeted alpha therapy becoming a gold standard treatment in oncology in the future.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A

The ever-growing rise of antibiotic resistance among bacterial pathogens is one of the top healthcare threats today. Although combination antibiotic therapies represent a potential approach to more efficiently combat infections caused by susceptible and drug-resistant bacteria, only a few known drug pairs exhibit synergy/cooperativity in killing bacteria. Here, we discover that well-known ribosomal antibiotics, hygromycin A (HygA) and macrolides, which target peptidyl transferase center and peptide exit tunnel, respectively, can act cooperatively against susceptible and drug-resistant bacteria. Remarkably, HygA slows down macrolide dissociation from the ribosome by 60-fold and enhances the otherwise weak antimicrobial activity of the newest-generation macrolide drugs known as ketolides against macrolide-resistant bacteria. By determining a set of high-resolution X-ray crystal structures of drug-sensitive wild-type and macrolide-resistant Erm-methylated 70S ribosomes in complex with three HygA-macrolide pairs, we provide a structural rationale for the binding cooperativity of these drugs and also uncover the molecular mechanism of overcoming Erm-type resistance by macrolides acting together with hygromycin A. Altogether our structural, biochemical, and microbiological findings lay the foundation for the subsequent development of synergistic antibiotic tandems with improved bactericidal properties against drug-resistant pathogens, including those expressing erm genes.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2010

Pharmacological Issues for Astronauts

Medication-induced side effects, called untoward effects by pharmacologists, can be a problem with any medication. Few therapies are perfectly specific for the desired physiological activity; rather they act on multiple biological targets and result in multiple physiological effects. There are several strategies that are employed to prevent, alleviate or counteract medication-induced side effects. The administered dose may be optimized to the lowest possible amount that provides the desired therapeutic effect, with the expectation that untoward effects will be minimized by a lower dose. Empirical trials of different therapies for a particular medical problem may be used in the hopes of finding a drug with minimal side effects for a particular patient, or at least of finding a set of side effects that the patient considers tolerable. If these two strategies have been exhausted, it may be possible to administer another medication to block or ameliorate side effects. A recent search of published scientific literature has revealed that there are medications used in spaceflight that seem to be associated with a significant number of reports of untoward effects. To prevent future medical problems and to improve the well-being and productivity of crew members, it would be best to eliminate (or at least reduce) untoward effects. Reports from the literature will be examined, with the aim of identifying a strategy for reducing untoward effects.

Wotring, Virginia E.↗
NASA NTRS2014

Combinatorial Multidomain Mesoporous Chips and a Method for Fractionation, Stabilization, and Storage of Biomolecules

A new fractionation device shows desirable features for exploratory screening and biomarker discovery. The constituent MSCs may be tailored for desired pore sizes and surface properties and for the sequestration and enrichment of extremely low abundant protein and peptides in desired ranges of the mass/charge spectrum. The MSCs are effective in yielding reproducible extracts from complex biological samples as small as 10 microliter in a time as short as 30 minutes. They are inexpensive to manufacture, and allow for scaled up production to attain the simultaneous processing of a large number of samples. The MSCs are multiplexed, label-free diagnostic tools with the potential of biological recognition moiety modification for enhanced specificity. The MSCs may store, protect and stabilize biological fluids, enabling the simplified and cost-effective collection and transportation of clinical samples. The MSC-based device may serve as a diagnostic tool to complement histopathology, imaging, and other conventional clinical techniques. The MSCs mediated identification of disease-specific protein signatures may help in the selection of personalized therapeutic combinations, in the real-time assessment of therapeutic efficacy and toxicity, and in the rational modulation of therapy based on the changes in the protein networks associated with the prognosis and the drug resistance of the disease.

Ferrari, Mauro↗
DOE OSTI2023

Discordant Clinical and Microbiological Outcomes Are Associated With Late Clinical Relapse in Clinical Trials for Complicated Urinary Tract Infections

Abstract Background Current US Food and Drug Administration guidance recommends that the primary endpoint for complicated urinary tract infection clinical trials be a composite of the clinical and microbiological responses, assessed at a fixed point after therapy. Although some participants meet the criteria for clinical success, they do not meet the criteria for microbiological eradication and are classified as treatment failures. These discordant outcomes have raised questions about the utility of the microbiological endpoint. Methods We analyzed participant data from 13 phase 3 clinical trials submitted to the US Food and Drug Administration (N = 4842). Outcomes were determined at the test of cure (TOC) visit, recommended to occur at least 5 days after therapy and at the late follow-up visit, recommended to occur 21 to 28 days after randomization. Clinical and microbiological success were defined as the resolution of complicated urinary tract infection symptoms present at study entry, with no new symptoms (clinical cure), and a reduction in density of the original pathogen to <103 CFU/mL on urine culture (microbiological eradication). Results Among included participants, 70.7% were concordant successes at the TOC visit, 18.0% were discordant failures (clinical cure/microbiological persistence), and 6.7% were concordant failures (clinical failure/microbiological persistence). Discordant participants were at an increased risk for clinical failure at the late follow-up visit, and the risk of late clinical failure increased with time. Conclusions Discordant clinical and microbiological outcomes at the TOC visit were associated with an increased risk of late clinical failure. Microbiological outcomes appear to be an important component of the endpoint.

Immunology↗