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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

Peptoid-based chelating ligands for selective metal chelation

The present disclosure provides peptoid-based chelating ligands, corresponding cyclic peptoids, and methods of making thereof. Functional groups may be tailored for high metal binding affinity and selectivity. The side chains of a cyclic peptoid according to the present disclosure may be selected based on, for example, high affinity for actinide or other metal ions, selectivity for actinide or other metal ions, the ability to recover a metal once it is bound to the peptoid, and whether the overall peptoid should be hydrophobic or hydrophilic. Unlike siderophores, peptoid-based chelating ligands of the present disclosure are not readily hydrolyzed under physiological conditions. Therefore, peptoid-based chelating ligands may be, for example, used to treat actinide (e.g., iron and lead) poisoning in vivo. Moreover, peptoid-based chelating ligands of the present disclosure may be used for medical imaging, chelation therapy, drug delivery, and separation technologies, for example.

Williams, Robert F.↗
DOE OSTI2023

Drug-Inducible Gene Therapy Effectively Reduces Spontaneous Seizures in Kindled Rats but Creates Off-Target Side Effects in Inhibitory Neurons

Over a third of patients with temporal lobe epilepsy (TLE) are not effectively treated with current anti-seizure drugs, spurring the development of gene therapies. The injection of adeno-associated viral vectors (AAV) into the brain has been shown to be a safe and viable approach. However, to date, AAV expression of therapeutic genes has not been regulated. Moreover, a common property of antiepileptic drugs is a narrow therapeutic window between seizure control and side effects. Therefore, a long-term goal is to develop drug-inducible gene therapies that can be regulated by clinically relevant drugs. In this study, a first-generation doxycycline-regulated gene therapy that delivered an engineered version of the leak potassium channel Kcnk2 (TREK-M) was injected into the hippocampus of male rats. Rats were electrically stimulated until kindled. EEG was monitored 24/7. Electrical kindling revealed an important side effect, as even low expression of TREK M in the absence of doxycycline was sufficient to cause rats to develop spontaneous recurring seizures. Treating the epileptic rats with doxycycline successfully reduced spontaneous seizures. Localization studies of infected neurons suggest seizures were caused by expression in GABAergic inhibitory neurons. In contrast, doxycycline increased the expression of TREK-M in excitatory neurons, thereby reducing seizures through net inhibition of firing. These studies demonstrate that drug-inducible gene therapies are effective in reducing spontaneous seizures and highlight the importance of testing for side effects with pro-epileptic stressors such as electrical kindling. These studies also show the importance of evaluating the location and spread of AAV-based gene therapies in preclinical studies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Longitudinal Preclinical Imaging Characterizes Extracellular Drug Accumulation After Radiation Therapy in the Healthy and Leukemic Bone Marrow Vascular Microenvironment

Recent initial findings suggest that radiation therapy improves blood perfusion and cellular chemotherapy uptake in mice with leukemia. However, the ability of radiation therapy to influence drug accumulation in the extracellular bone marrow tissue is unknown, due in part to a lack of methodology. This study developed longitudinal quantitative multiphoton microscopy (L-QMPM) to characterize the bone marrow vasculature (BMV) and drug accumulation in the extracellular bone marrow tissue before and after radiation therapy in mice bearing leukemia.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

HIV drug resistance during antiretroviral therapy scale-up in Uganda, 2012–19: a population-based, longitudinal study

Background With scale-up of antiretroviral therapy (ART) in sub-Saharan Africa, increasing pretreatment HIV drug resistance has been reported; however, the broader effect of ART expansion on population-level resistance patterns remains insufficiently quantified. We aimed to estimate the longitudinal prevalence of drug resistance and resistance-conferring mutations. Methods This study used data collected as part of the Rakai Community Cohort Study (RCCS), an open population-based census and cohort study conducted in southern Uganda. At each survey round, residents aged 15–49 years are invited to participate and receive a structured questionnaire that obtains sociodemographic, behavioural, and health information, including self-reported past and current ART use. Voluntary HIV testing is conducted using a rapid test algorithm and a venous blood sample. People with HIV provide samples for viral load quantification and deep sequencing. We analysed RCCS survey, HIV viral load, and deep sequencing (which was used to predict resistance) data from five survey rounds. The key outcomes were the population prevalence of viraemic people with HIV with non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), protease inhibitor, or multiclass resistance among all participants (regardless of HIV serostatus) in the 2015 and 2017 surveys. Prevalence of class-specific resistance and resistance-conferring substitutions were estimated using robust log-Poisson regression. Findings Between Aug 10, 2011, and Nov 4, 2020, there were 43 361 participants in the RCCS and 7923 (18·27%) people with HIV. Over five survey rounds, 93 622 participant visits occurred, among which 17 460 (18·65%) were from people with HIV. Over the analysis period, the median age of study participants remained similar (28 years [22–35] in 2012 and 29 years [21–38] in 2019). Sufficient data were available to reliably genotype 4072 (90·03%) of 4523 participant visits from 3407 people with HIV for at least one drug. Overall population prevalence of resistance contributed by viraemic pretreatment people with HIV decreased between 2012 and 2017 from 0·56% (95% CI 0·42–0·75) to 0·25% (0·18–0·33) for NNRTI and from 0·24% (0·15–0·37) to 0·05% (0·02–0·10) for NRTI (prevalence ratio 0·44 [0·29–0·68] for NNRTI and 0·21 [0·09–0·47] for NRTI). Between 2012 and 2017, NNRTI resistance among viraemic pretreatment people with HIV increased from 4·86% (3·69–6·42) to 9·61% (7·27–12·7; prevalence ratio 1·98 [1·34–2·91]). The prevalence of NNRTI and NRTI resistance was substantially higher among viraemic treatment-experienced people with HIV (51·49% [46·24–57·34] for NNRTI and 36·46% [30·06–44·22] for NRTI in 2017) than among pretreatment people with HIV. NNRTI and NRTI resistance was predominantly attributable to rtK103N and rtM184V. inT97A was observed at a similar prevalence among viraemic treatment-experienced (9·96% [6·41–15·48]) and viraemic pretreatment (10·56% [8·01–13·93]) people with HIV; no major dolutegravir resistance mutations were observed. Interpretation Despite rising NNRTI resistance among pretreatment people with HIV, overall population prevalence of pretreatment HIV drug-resistant viraemia decreased due to increasing ART uptake and viral suppression. This finding underscores the crucial role of achieving and maintaining high ART coverage in reducing transmission of drug-resistant HIV. The high prevalence of mutations conferring resistance to components of first-line ART regimens among viraemic people with HIV is potentially concerning. Funding National Institutes of Health, Johns Hopkins University Center for AIDS Research, Bill & Melinda Gates Foundation, and the US Centers for Disease Control and Prevention.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Regulatory Considerations in the Development of Radiation-Drug Combinations

Radiation therapy remains a fundamental treatment for patients with cancer. Despite an increasing number of targeted molecular therapies that are US Food and Drug Administration (FDA)-approved for the treatment of patients with metastatic disease, there has been very little progress made in terms of drugs used concurrently with radiation. This article reviews the existing regulatory framework in which cancer drugs may be developed for use in combination with radiation therapy from the perspective of the FDA. To briefly summarize: (1) nonclinical studies are a critical first step to ensure that drugs are safe for use in humans; however, additional nonclinical studies of a drug with radiation may not be required before a clinical trial in combination with radiation as long as the safety profile of the drug has been characterized in humans. The FDA determines the quality of evidence required before studying a drug in combination with radiation on a case-by-case basis. (2) Although often impractical to consider late toxicities during dose-escalation, late adverse events should be captured and taken into consideration when determining the final dose and schedule to take forward during drug development. (3) There are a number of expedited programs for cancer drug development, including accelerated approval, a conditional approval that allows for use of earlier clinical endpoints when the data suggests a clinically meaningful improvement over available therapy. (4) The Agency encourages sponsors to discuss their development plan with the appropriate FDA review division in formal regulatory meetings.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Moving Beyond the Standard of Care: Accelerate Testing of Radiation-Drug Combinations

Radiation therapy is a major treatment modality used in > 60% of cancer patients as definitive local treatment for inoperable locoregionally confined tumors and as palliative therapy. Although cytotoxic chemotherapy enhances the effectiveness of treatment, the benefit over radiation therapy alone is modest. There is a need to enhance the effectiveness of local tumor control over what sequentially or concurrently administered cytotoxic chemotherapy provides. Although many biological pathways are known to enhance the effectiveness of radiation therapy, there is currently a paucity of drugs approved for use in combination. Several clinical trials have tested the effectiveness of combining targeted agents or immunotherapies with radiation therapy, but the results of these trials have been negative, likely stemming from the relative lack of preclinical evidence using appropriate experimental standardization or model systems. Accelerating the identification of agents tested in an appropriate clinical context and experimental systems or models would greatly enhance the potential to bring forward early testing of drugs that would not only be safe but also more effective. This article provides an overview of the opportunities and challenges of developing therapeutics to combine with radiation therapy, and some guidance toward preclinical and early clinical testing to improve the chance that advanced phase testing of drug-radiation combinations would be successful in the long term.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Acoustics at the nanoscale (nanoacoustics): A comprehensive literature review. Part II: Nanoacoustics for biomedical imaging and therapy

We report in the past decade, acoustics at the nanoscale (i.e., nanoacoustics) has evolved rapidly with continuous and substantial expansion of capabilities and refinement of techniques. Motivated by research innovations in the last decade, for the first time, recent advancements of acoustics-associated nanomaterials/nanostructures and nanodevices for different applications are outlined in this comprehensive review, which is written in two parts. As part II of this two-part review, this paper concentrates on nanoacoustics in biomedical imaging and therapy applications, including molecular ultrasound imaging, photoacoustic imaging, ultrasound-mediated drug delivery and therapy, and photoacoustic drug delivery and therapy. Firstly, the recent developments of nanosized ultrasound and photoacoustic contrast agents as well as their various imaging applications are examined. Secondly, different types of nanomaterials/nanostructures as nanocarriers for ultrasound and photoacoustic therapies are discussed. Finally, a discussion of challenges and future research directions are provided for nanoacoustics in medical imaging and therapy.

47 OTHER INSTRUMENTATION↗
DOE OSTI2020

HIV-1 transmitted drug resistance surveillance: shifting trends in study design and prevalence estimates

HIV-1 transmitted drug resistance (TDR) prevalence increased during the initial years of the antiretroviral therapy (ART) global scale-up. Few studies have examined recent trends in TDR prevalence using published genetic sequences and described the characteristics of ART-naïve persons from whom these published sequences have been obtained. We identified 125 studies published between 2014 and 2019 for which HIV-1 reverse transcriptase (RT) with or without protease from ≥50 ART-naïve adult persons were submitted to the GenBank sequence database. The population characteristics and TDR prevalence were compared to those in 122 studies published in the preceding five years between 2009 and 2013. TDR prevalence was analysed using median study-level and person-level data. The 2009 to 2013 and 2014 to 2019 studies reported sequence data from 32,866 and 41,724 ART-naïve persons respectively. Studies from the low- and middle-income country (LMIC) regions in sub-Saharan Africa, South/Southeast Asia and Latin America/Caribbean accounted for approximately two-thirds of the studies during each period. Between the two periods, the proportion of studies from sub-Saharan Africa and from South/Southeast Asia countries other than China decreased from 43% to 32% and the proportion of studies performed at sentinel sites for recent HIV-1 infection decreased from 33% to 22%. Between 2014 and 2019, median study-level TDR prevalence was 4.1% in South/Southeast Asia, 6.0% in sub-Saharan Africa, 9.1% in Latin America/Caribbean, 8.5% in Europe and 14.2% in North America. In the person-level analysis, there was an increase in overall, NNRTI and two-class NRTI/NNRTI resistance in sub-Saharan Africa; an increase in NNRTI resistance in Latin America/Caribbean, and an increase in overall, NNRTI and PI resistance in North America. Overall, NNRTI and dual NRTI/NNRTI-associated TDR prevalence was significantly higher in sub-Saharan Africa studies published between 2014 and 2019 compared with those published between 2009 and 2013. The decreasing proportion of studies from the hardest hit LMIC regions and the shift away from sentinel sites for recent infection suggests that global TDR surveillance efforts and publication of findings require renewed emphasis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Mapping the proteogenomic landscape enables prediction of drug response in acute myeloid leukemia

Acute myeloid leukemia is a poor prognosis cancer commonly stratified by genetic aberrations, but these mutations are often heterogeneous and don’t always predict therapeutic response. Here we combine transcriptomic, proteomic, and phosphoproteomic datasets with ex vivo drug sensitivity data to help understand the underlying pathophysiology of AML beyond mutations. We measured the proteome and phosphoproteome of 210 patients and combined them with genomics and transcriptomic measurements to identify four proteogenomic subtypes that complemented existing genetic subtypes. We then built a predictor to classify samples into subtypes based on 147 molecular features and mapped them to a ‘landscape’. Each region of this landscape corresponded to specific drug response patterns. We then built a drug response prediction model to identify drugs that target distinct subtypes. We can ultimately use these models to predict drug treatment response and prioritize treatments. Finally, we extended our models and mapped a series of cell lines representing various stages of quizartinib resistance into our subtype landscape, predicting and experimentally validating a switch in sensitivity to venetoclax to panobinostat, two drugs with very different mechanisms than quizartinib. Our results show how multi-omics data together with drug sensitivity data can inform therapy stratification and drug combinations in AML.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1997

Prostaglandin E2 (PGE2) and risedronate was superior to PGE2 alone in maintaining newly added bone in the cortical bone site after withdrawal in older intact rats

The objects of this study were (1) to determine the effects of risedronate (Ris) and prostaglandin E2 (PGE2) alone and in combination, on tibial diaphyses of older intact female rats; and (2) to observe the fate of any extra bone if formed after withdrawal of the treatment. Nine-month-old female Sprague-Dawley rats were treated with 6 mg of PGE2/kg/day, 1 or 5 micrograms of Ris/kg twice a week, or 6 mg of PGE2/kg/day plus 1 or 5 micrograms of Ris/kg twice a week for the first 60 days and followed by vehicle injections for another 60 days. Cross-sections of double fluorescent labeled, undecalcified tibial diaphyses proximal to the tibiofibular junction were processed for histomorphometry. We found that: (1) neither the 1 microgram nor the 5 micrograms of Ris treatment in the 60-day on/60-day off group showed any histomorphometric differences from age-related controls; (2) while the 60 days of PGE2 treatment added extra cortical bone (6%) on the tibial shaft (due to stimulation of periosteal, endocortical, and marrow trabecular bone formation), the new endocortical and most of the new marrow trabecular bone were lost when treatment was withdrawn; however, the new periosteal bone remained; (3) PGE2 with Ris added the same amount of new bone to tibial diaphysis as did PGE2 alone and upon withdrawal, new marrow trabecular bone was lost but new periosteal and endocortical bones were preserved in PGE2 + 1 microgram of Ris on/off group. In contrast, all the new bone was maintained in the PGE2 + 5 micrograms of Ris on/off group; (4) PGE2 + Ris cotreatment failed to block the increase in cortical bone porosity induced by PGE2; and (5) in the PGE2 alone and PGE2 + 1 microgram of Ris on/off groups bone turnover was higher than that in the PGE2 + 5 micrograms of Ris on/off group. These results indicate that on/off treatment with PGE2 and Ris is superior to PGE2 alone in that it forms the same amount of new bone during treatment, but preserves more cortical bone during withdrawal. Depression of bone resorption and turnover were the tissue mechanisms responsible for this protection.

NASA Program Space Physiology and Countermeasures↗
DOE OSTI2020

Ion-Exchange Kinetics of Alpha-Zirconium Phosphate Nanoplatelets for Application in Targeted Alpha Therapy

The loading and kinetics of uptake for the inorganic ion-exchange material, α-zirconium phosphate, Zr(HPO 4 ) 2 •H 2 O, were investigated with ions relevant to targeted alpha therapy including natural Cs + (as a surrogate for 221 Fr), natural Bi 3+ (as a surrogate for 213 Bi), and natural La 3+ (as a surrogate for 225 Ac). The narrow interlayer spacing of the α-phase (d = 7.6 Å) was found not to be advantageous with respect to rapid ion exchange, while converting the material to the hydrated Na-phase (d = 12.2 Å) allowed ion exchange to proceed more quickly, reaching equilibrium in under an hour. High loading was achieved for all three ions, at 72 ± 4% for Cs + and 95 ± 5% for La 3+ at pH 3 and 108 ± 10% for Bi 3+ at pH 0.5. Leaching profiles of the loaded materials in a simulated human plasma environment of 10 mM carbonate buffer at pH 7.4 and 37°C, showed negligible release, with less than 1% in all cases. Furthermore, the ion-exchange properties and overall benign nature of zirconium phosphate highlight these materials as a promising platform for a targeted alpha therapy drug-delivery vehicle.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS1992

Lack of deleterious effect of slow-release sodium fluoride treatment on cortical bone histology and quality in osteoporotic patients

We evaluated the effects of intermittent slow-release sodium fluoride (SRNaF) and continuous calcium citrate therapy on cortical bone histology, reflection ultrasound velocity (material strength) and back-scattered electron image analysis (BEI) in 26 osteoporotic patients before and following therapy. All measurements were made on transiliac crest bone biopsies obtained before and following 2 years of therapy in each patient. For all 26 patients there were no significant changes in cortical bone histomorphometric parameters. In 15 patients in whom bone material quality was assessed by reflection ultrasound, there was no change in velocity (4000 +/- 227 SD to 4013 +/- 240 m/s). BEI disclosed no mineralization defects or the presence of woven bone. Mean atomic number (density) of bone increased slightly, but significantly (9.261 +/- 0.311 to 9.457 +/- 0.223, P = 0.031). While these changes are less marked than those observed for cancellous bone, they indicate that this form of therapy does not adversely affect cortical bone remodelling.

NASA Discipline Regulatory Physiology↗
DOE OSTI2025

C10-Benzoate Esters of Anhydrotetracycline Inhibit Tetracycline Destructases and Recover Tetracycline Antibacterial Activity

Tetracyclines (TCs) are an important class of antibiotics threatened by enzymatic inactivation. These tetracycline-inactivating enzymes, also known as tetracycline destructases (TDases), are a subfamily of class A flavin monooxygenases (FMOs) that catalyze hydroxyl group transfer and oxygen insertion (Baeyer–Villiger type) reactions on TC substrate scaffolds. Semisynthetic modification of TCs (e.g., tigecycline, omadacycline, eravacycline, and sarecycline) has proven effective in evading certain resistance mechanisms, such as ribosomal protection and efflux, but does not protect against TDase-mediated resistance. Here, we report the design, synthesis, and evaluation of a new series of 22 semisynthetic TDase inhibitors that explore D-ring substitution of anhydrotetracycline (aTC) including 14 C10-benzoate ester and eight C9-benzamides. Overall, the C10-benzoate esters displayed enhanced bioactivity and water solubility compared to the corresponding C9-benzamides featuring the same heterocyclic aryl side chains. The C10-benzoate ester derivatives of aTC were prepared in a high-yield one-step synthesis without the need for protecting groups. The C10-esters are water-soluble, stable toward hydrolysis, and display dose-dependent rescue of tetracycline antibiotic activity in E. coli expressing two types of tetracycline destructases, represented by TetX7 (Type 1) and Tet50 (Type 2). The best inhibitors recovered tetracycline antibiotic activity at concentrations as low as 2 μM, producing synergistic scores <0.5 in the fractional inhibitory concentration index (FICI) against TDase-expressing strains of E. coli and clinical P. aeruginosa. The C10-benzoate ester derivatives of aTC reported here are promising new leads for the development of tetracycline drug combination therapies to overcome TDase-mediated antibiotic resistance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology

Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX). Genomic analysis was performed on all PDX-tumor pairs. Selected PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells. We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%), and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (>90% viability at 48 h), good (>50%), or unusable (<50%). We evaluated drug response to “robust” or “good” microtissues, namely MN-2, JH-2-002, JH-2-079-c, and WU-225. Drug response ex vivo predicted drug response in vivo, and enhanced drug effects were observed in select models. These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Spatial inequities in access to medications for treatment of opioid use disorder highlight scarcity of methadone providers under counterfactual scenarios

Access to treatment and medication for opioid use disorder (MOUD) is essential in reducing opioid use and associated behavioral risks, such as syringe sharing among persons who inject drugs (PWID). Syringe sharing among PWID carries high risk of transmission of serious infections such as hepatitis C and HIV. MOUD resources, such as methadone provider clinics, however, are often unavailable to PWID due to barriers like long travel distance to the nearest methadone provider and the required frequency of clinic visits. The goal of this study is to examine the uncertainty in the effects of travel distance in initiating and continuing methadone treatment and how these interact with different spatial distributions of methadone providers to impact co-injection (syringe sharing) risks. A baseline scenario of spatial access was established using the existing locations of methadone providers in a geographical area of metropolitan Chicago, Illinois, USA. Next, different counterfactual scenarios redistributed the locations of methadone providers in this geographic area according to the densities of both the general adult population and according to the PWID population per zip code. We define different reasonable methadone access assumptions as the combinations of short, medium, and long travel distance preferences combined with three urban/suburban travel distance preference. Our modeling results show that when there is a low travel distance preference for accessing methadone providers, distributing providers near areas that have the greatest need (defined by density of PWID) is best at reducing syringe sharing behaviors. However, this strategy also decreases access across suburban locales, posing even greater difficulty in regions with fewer transit options and providers. As such, without an adequate number of providers to give equitable coverage across the region, spatial distribution cannot be optimized to provide equitable access to all PWID. Our study has important implications for increasing interest in methadone as a resurgent treatment for MOUD in the United States and for guiding policy toward improving access to MOUD among PWID.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

The effect of enrofloxacin on enteric Escherichia coli : Fitting a mathematical model to in vivo data

Antimicrobial drugs administered systemically may cause the emergence and dissemination of antimicrobial resistance among enteric bacteria. To develop logical, research-based recommendations for food animal veterinarians, we must understand how to maximize antimicrobial drug efficacy while minimizing risk of antimicrobial resistance. Our objective is to evaluate the effect of two approved dosing regimens of enrofloxacin (a single high dose or three low doses) on Escherichia coli in cattle. We look specifically at bacteria above and below the epidemiological cutoff (ECOFF), above which the bacteria are likely to have an acquired or mutational resistance to enrofloxacin. We developed a differential equation model for the antimicrobial drug concentrations in plasma and colon, and bacteria populations in the feces. The model was fit to animal data of drug concentrations in the plasma and colon obtained using ultrafiltration probes. Fecal E. coli counts and minimum inhibitory concentrations were measured for the week after receiving the antimicrobial drug. We predict that the antimicrobial susceptibility of the bacteria above the ECOFF pre-treatment strongly affects the composition of the bacteria following treatment. Faster removal of the antimicrobial drugs from the colon throughout the study leads to improved clearance of bacteria above the ECOFF in the low dose regimen. If we assume a fitness cost is associated with bacteria above the ECOFF, the increased fitness costs leads to reduction of bacteria above the ECOFF in the low dose study. These results suggest the initial E. coli susceptibility is a strong indicator of how steers respond to antimicrobial drug treatment.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

In search of autophagy biomarkers in breast cancer: Receptor status and drug agnostic transcriptional changes during autophagy flux in cell lines

Autophagy drives drug resistance and drug-induced cancer cell cytotoxicity. Targeting the autophagy process could greatly improve chemotherapy outcomes. The discovery of specific inhibitors or activators has been hindered by challenges with reliably measuring autophagy levels in a clinical setting. We investigated drug-induced autophagy in breast cancer cell lines with differing ER/PR/Her2 receptor status by exposing them to known but divergent autophagy inducers each with a unique molecular target, tamoxifen, trastuzumab, bortezomib or rapamycin. Differential gene expression analysis from total RNA extracted during the earliest sign of autophagy flux showed both cell- and drug-specific changes. We analyzed the list of differentially expressed genes to find a common, cell- and drug-agnostic autophagy signature. Twelve mRNAs were significantly modulated by all the drugs and 11 were orthogonally verified with Q-RT-PCR (Klhl24, Hbp1, Crebrf, Ypel2, Fbxo32, Gdf15, Cdc25a, Ddit4, Psat1, Cd22, Ypel3). The drug agnostic mRNA signature was similarly induced by a mitochondrially targeted agent, MitoQ. In-silico analysis on the KM-plotter cancer database showed that the levels of these mRNAs are detectable in human samples and associated with breast cancer prognosis outcomes of Relapse-Free Survival in all patients (RSF), Overall Survival in all patients (OS), and Relapse-Free Survival in ER + Patients (RSF ER + ). High levels of Klhl24, Hbp1, Crebrf, Ypel2, CD22 and Ypel3 were correlated with better outcomes, whereas lower levels of Gdf15, Cdc25a, Ddit4 and Psat1 were associated with better prognosis in breast cancer patients. This gene signature uncovers candidate autophagy biomarkers that could be tested during preclinical and clinical studies to monitor the autophagy process.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2002

Subcutaneous administration of insulin-like growth factor (IGF)-II/IGF binding protein-2 complex stimulates bone formation and prevents loss of bone mineral density in a rat model of disuse osteoporosis

Elevated serum levels of insulin-like growth factor binding protein-2 (IGFBP-2) and a precursor form of IGF-II are associated with marked increases in bone formation and skeletal mass in patients with hepatitis C-associated osteosclerosis. In vitro studies indicate that IGF-II in complex with IGFBP-2 has high affinity for bone matrix and is able to stimulate osteoblast proliferation. The purpose of this study was to determine the ability of the IGF-II/IGFBP-2 complex to increase bone mass in vivo. Osteopenia of the femur was induced by unilateral sciatic neurectomy in rats. At the time of surgery, 14-day osmotic minipumps containing vehicle or 2 microg IGF-II+9 microg IGFBP-2/100g body weight/day were implanted subcutaneously in the neck. Bone mineral density (BMD) measurements were taken the day of surgery and 14 days later using a PIXImus small animal densitometer. Neurectomy of the right hindlimb resulted in a 9% decrease in right femur BMD (P<0.05 vs. baseline). This loss in BMD was completely prevented by treatment with IGF-II/IGFBP-2. On the control limb, there was no loss of BMD over the 14 days and IGF-II/IGFBP-2 treatment resulted in a 9% increase in left femur BMD (P<0.05). Bone histomorphometry indicated increases in endocortical and cancellous bone formation rates and in trabecular thickness. These results demonstrate that short-term administration of the IGF-II/IGFBP-2 complex can prevent loss of BMD associated with disuse osteoporosis and stimulate bone formation in adult rats. Furthermore, they provide proof of concept for a novel anabolic approach to increasing bone mass in humans with osteoporosis.

NASA Discipline Regulatory Physiology↗