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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 307 records · Page 17
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Fatty acid-mediated signaling as a target for developing type 1 diabetes therapies

Type 1 diabetes (T1D) is an autoimmune disease in which pro-inflammatory and cytotoxic signaling drive the death of the insulin-producing ß cells. This complex signaling is regulated in part by fatty acids and their bioproducts, making them excellent therapeutic targets. We provide an overview of the fatty acid actions on ß cells by discussing how they can cause lipotoxicity or regulate inflammatory response during insulitis. Additionally, we also discuss how diet can affect the availability of fatty acids and disease development. Finally, we discuss development avenues that need further exploration. Fatty acids, such as hydroxyl fatty acids, ω-3 fatty acids and their downstream products, are druggable candidates that promote protective signaling. Inhibitors and antagonists of enzymes and receptors of arachidonic acid and free fatty acid metabolites, which cause pro-inflammatory and cytotoxic responses, have the potential to be developed as therapeutic targets also. Further, because diet is the main source of fatty acid intake in humans, balancing protective and pro-inflammatory/cytotoxic fatty acid levels through dietary therapy may have beneficial effects, delaying T1D progression. Therefore, therapeutic interventions targeting fatty acid signaling hold potential as avenues to treat T1D.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Shielding Analysis of a Preclinical Bremsstrahlung X-ray FLASH Radiotherapy System within a Clinical Radiation Therapy Vault

A preclinical radiotherapy system producing FLASH dose rates with 12 MV bremsstrahlung x rays is being developed at Stanford University and SLAC National Accelerator Laboratory. Because of the high expected workload of 6,800 Gy w –1 at the isocenter, an efficient shielding methodology is needed to protect operators and the public while the preclinical system is operated in a radiation therapy vault designed for 6 MV x rays. Here, in this study, an analysis is performed to assess the shielding of the local treatment head and radiation vault using the Monte Carlo code FLUKA and the empirical methodology given in the National Council on Radiation Protection and Measurements Report 151. Two different treatment head shielding designs were created to compare single-layer and multilayer shielding methodologies using high-Z and low-Z materials. The multilayered shielding methodology produced designs with a 17% reduction in neutron fluence leaking from the treatment head compared to the single layered design of the same size, resulting in a decreased effective dose to operators and the public. The conservative assumptions used in the empirical methods can lead to over-shielding when treatment heads use polyethylene or multilayered shielding. High-Z/Low-Z multilayered shielding optimized via Monte Carlo is shown to be effective in the case of treatment head shielding and provide more effective shielding design for external beam radiotherapy systems that use 12 MV bremsstrahlung photons. Modifications to empirical methods used in the assessment of MV radiotherapy systems may be warranted to capture the effects of polyethylene in treatment head shielding.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2023

Locoregional Treatment of Glioblastoma With Targeted α Therapy: [213Bi]Bi-DOTA–Substance P Versus [225Ac]Ac-DOTA–Substance P—Analysis of Influence Parameters

Background Glioblastoma (GB) is the most malignant primary brain tumor. Therefore, introduction of new treatment options is critically important. The aim of this study was to assess local treatment with α emitters [ 213 Bi]Bi-DOTA–substance P (SP) and [ 225 Ac]Ac-DOTA-SP. Methods Treatment was performed as salvage therapy in patients with recurrent primary and secondary GB. [ 213 Bi]Bi-DOTA-SP with injected activity 1.85 GBq per cycle was used in 20 primary (48.2 ± 11.8 years old) and in 9 secondary (38.8 ± 10.8 years old) GB patients and [ 225 Ac]Ac-DOTA-SP in 15 primary (45.1 ± 9.9 years old) and in 6 secondary (37.8 ± 6.4 years old) GB patients with a dose escalation scheme (10, 20, and 30 MBq). Results Local treatment with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP was well tolerated with only few adverse effects. There was no statistically significant difference between [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP groups in survival parameters. For primary GB, survival parameters of patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows(in months): progression-free survival time, 2.7 versus 2.4; OS-d (overall survival from time of diagnosis to death from any cause), 23.6 versus 21.0; OS-t (overall survival from the start of treatment to death from any cause), 7.5 versus 5.0; and OS-r (overall survival from recurrence in primary tumors to death from any cause), 10.9 versus 12.0. Survival parameters of secondary GB patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows (in months): progression-free survival time, 5.8 versus 2.4; OS-d, 52.3 versus 65.0; OS-t, 16.4 versus 16.0; and OS-c (overall survival from conversion into secondary GB multiforme to death from any cause), 18.4 versus 36.0. Conclusions The similarity results of 213 Bi or 225 Ac may suggest that the local treatment of brain tumors can be greatly simplified. The experience to date shows that local radioisotope treatment of brain tumors requires further dosimetry studies, taking into account the complexity of biological processes.

Radiology, Nuclear Medicine & Medical Imaging↗
DOE OSTI2022

Mechanical and Thermal Analysis of an HTS Superconducting Magnet for an Achromatic Gantry for Proton Therapy

The mechanical and thermal analysis of the superconducting magnets, forming an innovative fixed-field bending section for use in a proton therapy gantry, is presented here. In this work, the design concept has a large momentum acceptance, covering the full proton energy range of 70 to 220 MeV with fixed field in the superconducting magnets, and uses a simple magnet geometry based on double-pancake high temperature superconductor coils. The main planned steps for the assembly and fabrication of the magnets are discussed. The mechanical analyses of the magnet, with emphasis on the stress state of the conductor during the powering of the magnet, is here described. The thermal analysis investigating the adequacy of the copper structure surrounding the conductor to extract the heat deposited in the conductor during powering is also discussed in detail.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2026

Magnetic Field Mapping of a 2.5 T Fixed-Field HTS Gantry Magnet for Proton Therapy

We present results from testing a high-temperature superconducting (HTS) magnet prototype for proton therapy. This magnet is specifically designed for a novel rotating gantry capable of delivering the entire proton beam energy range (70225 MeV) while maintaining a fixed magnetic field in the superconducting magnets. The gantry layout simplifies the magnet design, enabling the use of straight, flat racetrack Bi-2223 (DI-BSCCO) coil technology and operation at higher temperatures (1015 K). The magnet has a non-linear field distribution for bending and focusing the proton beams. To validate this feature, we developed a system for measuring the magnetic field distribution in the magnet aperture. We present the design of this hall probe array and experimental results from two different magnet tests at 4.2 K in a liquid helium bath. These results are compared with the simulated field distribution and discussed in the context of the required field quality for the application.

Mosat, M↗
DOE OSTI2025

Associations between hormone therapy use and tau accumulation in brain regions vulnerable to Alzheimer’s disease

Elucidating the downstream impact of exogenous hormones on the aging brain will have far-reaching consequences for understanding why Alzheimer’s disease (AD) predominates in women almost twofold over men. We tested the extent to which menopausal hormone therapy (HT) use is associated with later-life amyloid-β (Aβ) and tau accumulation using PET onN = 146 baseline clinically normal women, aged 51 to 89 years. Women were scanned over a 4.5-year (SD, 2.1; range, 1.3 to 10.4) and 3.5-year (SD, 1.5; range, 1.2 to 8.1) period for Aβ and tau, respectively, ~14 years after the initiation of HT. In older women (aged >70 years), HT users exhibited faster regional tau accumulation relative to non-users, localized to the entorhinal cortex and the inferior temporal and fusiform gyri, with an indirect effect of HT on cognitive decline through regional tau accumulation. In younger women (aged <70 years), HT associations with tau accumulation were negligible. Findings are relevant for optimizing menopausal treatment guidelines.

Science & Technology - Other Topics↗
DOE OSTI2025

The decay of HIV under anti-retroviral therapy is biphasic even in humanized mice with just T cells

HIV-1 plasma viral load decays in a biphasic manner during antiretroviral therapy (ART). It was hypothesized that this is due to infection of different cell types, namely CD4+ T cells and macrophages. We studied this possibility directly by modeling the decay of HIV-1 in humanized mice. We utilized previously published data from humanized T-cell only mice (TOM) and myeloid-only mice (MOM) infected with HIV-1 and treated with a potent ART regimen. Viral load decay dynamics were modeled using either a single or a biexponential decay fitted using nonlinear mixed effects techniques. Fits were compared using the corrected Bayesian information criterion (BICc). In TOM, the biphasic model was significantly better than a single-phase decay model (ΔBICc ≈ 16) despite additional parameters. In MOM, the biphasic decay was statistically better, but there was substantial uncertainty because the virus goes below detection very fast. The first-phase half-life was consistent between groups (1.2 days in MOM and 1.3 days in TOM) and similar to the half-life estimated in human infection. The second-phase decay in these mice was minimal likely due to low initial viral loads. Additional analyses with mice containing both CD4+ T cells and macrophages or X4-tropic virus-infected MOM mice confirmed the biphasic pattern, demonstrating the robustness of this result. The biphasic decline in HIV-1 occurs, even with only CD4+ T cells, refuting the hypothesis that distinct cell populations (CD4+ T cells and macrophages) drive each decay phase. These findings support an alternative model in which the observed dynamics arise from intrinsic properties of the viral infection lifecycle rather than from cellular compartmentalization.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL

Activated B cell–like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11–BCL10–MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

VEGFA165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss

Millions of people are affected by hearing loss. Hearing loss is frequently caused by noise or aging and often associated with loss of pericytes. Pericytes populate the small vessels in the adult cochlea. However, their role in different types of hearing loss is largely unknown. Using an inducible and conditional pericyte depletion mouse model and noise-exposed mouse model, we show that loss of pericytes leads to marked changes in vascular structure, in turn leading to vascular degeneration and hearing loss. In vitro, using advanced tissue explants from pericyte fluorescence reporter models combined with exogenous donor pericytes, we show that pericytes, signaled by VEGF isoform A165 (VEGFA165), vigorously drive new vessel growth in both adult and neonatal mouse inner ear tissue. In vivo, the delivery of an adeno-associated virus serotype 1–mediated (AAV1–mediated) VEGFA165 viral vector to pericyte-depleted or noise-exposed animals prevented and regenerated lost pericytes, improved blood supply, and attenuated hearing loss. These studies provide the first clear-cut evidence that pericytes are critical for vascular regeneration, vascular stability, and hearing in adults. The restoration of vascular function in the damaged cochlea, including in noise-exposed animals, suggests that VEGFA165 gene therapy could be a new strategy for ameliorating vascular associated hearing disorders.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Unraveling Vulnerabilities in Endocrine Therapy-Resistant HER2+/ER+ Breast Cancer

Abstract Breast tumors overexpressing human epidermal growth factor receptor (HER2) confer intrinsic resistance to endocrine therapy (ET), and patients with HER2/estrogen receptor–positive (HER2+/ER+) breast cancer (BCa) are less responsive to ET than HER2–/ER+. However, real-world evidence reveals that a large subset of patients with HER2+/ER+ receive ET as monotherapy, positioning this treatment pattern as a clinical challenge. In the present study, we developed and characterized 2 in vitro models of ET-resistant (ETR) HER2+/ER+ BCa to identify possible therapeutic vulnerabilities. To mimic ETR to aromatase inhibitors (AIs), we developed 2 long-term estrogen deprivation (LTED) cell lines from BT-474 (BT474) and MDA-MB-361 (MM361). Growth assays, PAM50 subtyping, and genomic and transcriptomic analyses, followed by validation and functional studies, were used to identify targetable differences between ET-responsive parental and ETR-LTED HER2+/ER+ cells. Compared to their parental cells, MM361 LTEDs grew faster, lost ER, and increased HER2 expression, whereas BT474 LTEDs grew slower and maintained ER and HER2 expression. Both LTED variants had reduced responsiveness to fulvestrant. Whole-genome sequencing of aggressive MM361 LTEDs identified mutations in genes encoding transcription factors and chromatin modifiers. Single-cell RNA sequencing demonstrated a shift towards non-luminal phenotypes, and revealed metabolic remodeling of MM361 LTEDs, with upregulated lipid metabolism and ferroptosis-associated antioxidant genes, including GPX4. Combining a GPX4 inhibitor with anti-HER2 agents induced significant cell death in both MM361 and BT474 LTEDs. The BT474 and MM361 AI-resistant models capture distinct phenotypes of HER2+/ER+ BCa and identify altered lipid metabolism and ferroptosis remodeling as vulnerabilities of this type of ETR BCa.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Peripheral Blood Transcript Signatures after Internal 131 I-mIBG Therapy in Relapsed and Refractory Neuroblastoma Patients Identifies Early and Late Biomarkers of Internal 131 I Exposures

131 I-metaiodobenzylguanidine ( 131 I-mIBG) is a targeted radiation therapy developed for the treatment of advanced neuroblastoma. We have previously shown that this patient cohort can be used to predict absorbed dose associated with early 131 I exposure, 72 h after treatment. We now expand these studies to identify gene expression differences associated with 131 I-mIBG exposure 15 days after treatment. Total RNA from peripheral blood lymphocytes was isolated from 288 whole blood samples representing 59 relapsed or refractory neuroblastoma patients before and after 131 I-mIBG treatment. We found that several transcripts predictive of early exposure returned to baseline levels by day 15, however, selected transcripts did not return to baseline. At 72 h, all 17 selected pathway-specific transcripts were differentially expressed. Transcripts CDKN1A (P < 0.000001), FDXR (P < 0.000001), DDB2 (P < 0.000001), and BBC3 (P < 0.000001) showed the highest up-regulation at 72 h after 131 I-mIBG exposure, with mean log2 fold changes of 2.55, 2.93, 1.86 and 1.85, respectively. At day 15 after 131I-mIBG, 11 of the 17 selected transcripts were differentially expressed, with XPC, STAT5B, PRKDC, MDM2, POLH, IGF1R, and SGK1 displaying significant up-regulation at 72 h and significant down-regulation at day 15. Interestingly, transcripts FDXR (P = 0.01), DDB2 (P = 0.03), BCL2 (P = 0.003), and SESN1 (P < 0.0003) maintained differential expression 15 days after 131 I-mIBG treatment. These results suggest that transcript levels for DNA repair, apoptosis, and ionizing radiation-induced cellular stress are still changing by 15 days after 131 I-mIBG treatment. Our studies showcase the use of biodosimetry gene expression panels as predictive biomarkers following early (72 h) and late (15 days) internal 131 I exposure. Our findings also demonstrate the utility of our transcript panel to differentiate exposed from non-exposed individuals up to 15 days after exposure from internal 131 I.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2023

Production of Radioisotopes of Scandium for Imaging and Therapy (Final Report)

The theranostic approach is a powerful technique that enables scientists and physicians to diagnose and treat diseases using the same targeting moiety labeled with radionuclides for imaging and therapy. A challenge behind synthesizing and evaluating these theranostic radiopharmaceuticals lies in the production of suitable radionuclides. This study aimed to investigate the production of high radionuclidic purity 43 Sc from enriched [ 46 Ti]TiO 2 for Positron Emission Tomography (PET) and 47 Sc from enriched [ 50 Ti]TiO 2 for targeted radiotherapy, as well as establish a target recycling technique for continued production of these radionuclides. Methods: Targets were prepared with 100 mg of either enriched [ 46 Ti]TiO 2 or [ 50 Ti]TiO 2 , pressed into pellets, and placed into Ta target holders with a 0.127 mm natTi cover foil. The 46 Ti targets were bombarded with 18 MeV protons at 20 µA for 1.5 h, while 50Ti targets were bombarded with 24 MeV protons at 20 µA for 4 or 8 h. The radioscandium nuclides were purified using branched N, N, N’, N’ -tetra-2-ethylhexyldiglycolamide (DGA) resin. The titanium targets were recycled by precipitating the dissolved Ti collected from the column effluent and wash streams, pH adjustment, vacuum filtration, and then drying the solid at 250 °C prior to reforming the target for the subsequent bombardment. The apparent molar activity of the isolated radioscandiums was analyzed by titration with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The relative imaging performance of 18 F, 43 Sc, and 68 Ga were analyzed with PET images acquired with 30-min static scans. Results: The average radioscandium recovery for 43Sc was 91.7 ± 7.4 %, with a radionuclidic purity of 98.8 %. The average recovery of 47Sc was 89.9 ± 3.9 %, with a radionuclidic purity of 90.8%. The average recovery of enriched TiO2 was 96 ± 4.0 %. The highest apparent molar activity for [43Sc]Sc-DOTA was 23.2 GBq/µmol and 3.39 GBq/µmol for [ 47 Sc]Sc-DOTA. The order of PET resolution from highest to lowest was 18 F > 43 Sc > 68 Ga. Conclusions: This work demonstrates the feasibility of using enriched recycled [ 46 Ti]TiO 2 and [ 50 Ti]TiO 2 targets for the production of the 43 Sc and 47 Sc theranostic isotope pair in high purity.

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗
DOE OSTI2025

Effect of in utero and lactational exposure to antiretroviral therapy on the gut microbial composition and metabolic function in aged rat offspring

Despite the highly effective impact of antiretroviral therapy (ART) in reducing mother-to-child transmission of human immunodeficiency virus (HIV), there are concerns of long-term impacts of ART on the health of the offspring. The implications of perinatal exposure to antiviral drugs on the gut bacterial population and metabolic function in the offspring is unclear but may influence health outcomes given the various reported effects of the microbiome in human health. This study aims to gain insight into the potential effect ofin uteroand lactational exposure to ART on gut microbiota populations and short‐chain fatty acids (SCFAs) production in aged rat offspring. Pregnant rats were administered a combination of antiretroviral drugs (abacavir/dolutegravir/lamivudine) at two different dose levels during gestation and throughout lactation, and the fecal bacterial abundance and SCFA levels of the offspring were analyzed when they reached 12 months of age. Our results showed dose-dependent and sex-based differences in fecal microbial abundance at various taxonomic levels. Specifically, we found a decline inFirmicutesin males, and an increase inActinobacteriaamong males and females. Furthermore, a sex-specific distribution reorganization ofLactobacillus,Bifidobacterium, andAkkermansiawas identified. No significant difference in the concentration of prominent SCFAs and IgA levels were identified. These findings provide preliminary information indicating the need to evaluate perinatal effects of ART more comprehensively on the gut bacterial and metabolic function in future studies, and their potential role in offspring health outcomes.

Research & Experimental Medicine↗
DOE OSTI2022

A Novel DNA Repair Gene Signature for Immune Checkpoint Inhibitor-Based Therapy in Gastric Cancer

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responding to immunotherapy. The relationships between tumor DNA damage response, patient immune system and immunotherapy have recently attracted attention. Accumulating evidence suggests that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsive to immunotherapies, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of the DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of patients with gastric adenocarcinoma, using publicly available datasets. The results demonstrated that DRGS high score patients showed significantly better therapeutic outcomes for ICB compared to DRGS low score patients (p < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocyte infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival, as compared to the low-score patients. Results obtained from HPA and IHC supported significant dysregulation of the genes in DRGS in gastric cancer tissues, and a positive correlation in protein expression between DRGS and PD-L1. Therefore, the DRGS scoring system may have implications in tailoring immunotherapy in gastric cancers. A preprint has previously been published (Yuan et al., 2021).

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Prospective Study Reveals Host Microbial Determinants of Clinical Response to Fecal Microbiota Transplant Therapy in Type 2 Diabetes Patients

Increasing evidence shows that alterations in gut microbiome (GM) contribute to the development of type 2 diabetes mellitus (T2DM), and fecal microbiota transplantation (FMT) successfully treats various human diseases. However, the benefits of FMT therapy to T2DM patients remain unknown. We enrolled 17 patients with T2DM for nonblinded, one-armed intervention trial of FMT. A total of 20 healthy individuals were recruited as the baseline control. HbA1c% and metabolic parameter change were evaluated in 17 T2DM patients 12 weeks after they received FMT from healthy donors. The GM composition was characterized by 16S rRNA gene amplicon sequencing from fecal samples prior to and 12 weeks after FMT treatment. We found that the GM of T2DM patients was reconstituted by FMT. We observed a statistically significant decrease in HbA1c% (from 7.565 ± 0.148 to 7.190 ± 0.210, p<0.01), blood glucose (from 8.483 ± 0.497 to 7.286 ± 0.454 mmol/L, p<0.01), and uric acid (from 309.4 ± 21.5 to 259.1 ± 15.8 µmol/L, p<0.01) while a significant increase in postprandial C-peptide (from 4.503 ± 0.600 to 5.471 ± 0.728 ng/ml, p<0.01) at 12 weeks after FMT. Closely evaluating the changes in these assays, we found individual variability in response to FMT treatment. Out of 17 T2DM patients, 11 were found to significantly improve T2DM symptoms. The FMT responders have significantly higher levels of the family Rikenellaceae and the genus Anaerotruncus (family Ruminococcaceae) in their pretreated fecal in comparison to nonresponders, which could predict the clinical response with an area under the curve of 0.83. Our findings suggest that certain T2DM patients can potentially benefit from FMT, and the pretreated abundance of Rikenellaceae and Anaerotruncus in the fecal of patients may serve as potential biomarkers for selecting T2DM patients to receive FMT.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

The key role of the ferroptosis mechanism in neurological diseases and prospects for targeted therapy

Neurological disorders represent a major global health concern owing to their intricate pathological processes. Ferroptosis, defined as a form of cell death that is reliant on iron, has been closely linked to various neurological conditions. The fundamental process underlying ferroptosis is defined by the excessive buildup of iron ions, which initiates lipid peroxidation processes leading to cellular demise. Neurons, as highly metabolically active cells, are susceptible to oxidative stress, and imbalances in iron metabolism can directly initiate the ferroptosis process. In neurodegenerative disorders like Alzheimer’s disease and Parkinson’s disease, ferroptosis driven by iron accumulation represents a fundamental pathological connection. Although the connection between ferroptosis and neurological diseases is clear, clinical application still faces challenges, such as precise regulation of iron metabolism, development of specific drugs, and assessment of efficacy. The limited comprehension of the ferroptosis mechanism hinders the development of personalized treatment approaches. Consequently, subsequent investigations must tackle these obstacles to facilitate the clinical application of ferroptosis-associated therapies in neurological disorders. This article provides a comprehensive overview of the most recent advancements regarding the underlying mechanisms of ferroptosis. Subsequently, the study investigates the mechanistic contributions of ferroptosis within the nervous system. In conclusion, we evaluate and deliberate on targeted therapeutic strategies associated with ferroptosis and neurological disorders.

Xie, Chenyu↗
DOE OSTI2022

High Accuracy Indicators of Androgen Suppression Therapy Failure for Prostate Cancer—A Modeling Study

Prostate cancer is a serious public health concern in the United States. The primary obstacle to effective long-term management for prostate cancer patients is the eventual development of treatment resistance. Due to the uniquely chaotic nature of the neoplastic genome, it is difficult to determine the evolution of tumor composition over the course of treatment. Hence, a drug is often applied continuously past the point of effectiveness, thereby losing any potential treatment combination with that drug permanently to resistance. If a clinician is aware of the timing of resistance to a particular drug, then they may have a crucial opportunity to adjust the treatment to retain the drug’s usefulness in a potential treatment combination or strategy. In this study, we investigate new methods of predicting treatment failure due to treatment resistance using a novel mechanistic model built on an evolutionary interpretation of Droop cell quota theory. We analyze our proposed methods using patient PSA and androgen data from a clinical trial of intermittent treatment with androgen deprivation therapy. Our results produce two indicators of treatment failure. The first indicator, proposed from the evolutionary nature of the cancer population, is calculated using our mathematical model with a predictive accuracy of 87.3% (sensitivity: 96.1%, specificity: 65%). The second indicator, conjectured from the implication of the first indicator, is calculated directly from serum androgen and PSA data with a predictive accuracy of 88.7% (sensitivity: 90.2%, specificity: 85%). Our results demonstrate the potential and feasibility of using an evolutionary tumor dynamics model in combination with the appropriate data to aid in the adaptive management of prostate cancer.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

EpiPro, a Novel, Synthetic, Activity-Regulated Promoter That Targets Hyperactive Neurons in Epilepsy for Gene Therapy Applications

Epileptogenesis is characterized by intrinsic changes in neuronal firing, resulting in hyperactive neurons and the subsequent generation of seizure activity. These alterations are accompanied by changes in gene transcription networks, first with the activation of early-immediate genes and later with the long-term activation of genes involved in memory. Our objective was to engineer a promoter containing binding sites for activity-dependent transcription factors upregulated in chronic epilepsy (EpiPro) and validate it in multiple rodent models of epilepsy. First, we assessed the activity dependence of EpiPro: initial electrophysiology studies found that EpiPro-driven GFP expression was associated with increased firing rates when compared with unlabeled neurons, and the assessment of EpiPro-driven GFP expression revealed that GFP expression was increased ~150× after status epilepticus. Following this, we compared EpiPro-driven GFP expression in two rodent models of epilepsy, rat lithium/pilocarpine and mouse electrical kindling. In rodents with chronic epilepsy, GFP expression was increased in most neurons, but particularly in dentate granule cells, providing in vivo evidence to support the “breakdown of the dentate gate” hypothesis of limbic epileptogenesis. Finally, we assessed the time course of EpiPro activation and found that it was rapidly induced after seizures, with inactivation following over weeks, confirming EpiPro’s potential utility as a gene therapy driver for epilepsy.

60 APPLIED LIFE SCIENCES↗