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At least 1,297 records · Page 72

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DOE OSTI2024

The SEMA3F-NRP1/NRP2 axis is a key factor in the acquisition of invasive traits in in situ breast ductal carcinoma

A better understanding of ductal carcinoma in situ (DCIS) is urgently needed to identify these preinvasive lesions as distinct clinical entities. Semaphorin 3F (SEMA3F) is a soluble axonal guidance molecule, and its coreceptors Neuropilin 1 (NRP1) and NRP2 are strongly expressed in invasive epithelial BC cells. We utilized two cell line models to represent the progression from a healthy state to the mild-aggressive or ductal carcinoma in situ (DCIS) stage and, ultimately, to invasive cell lines. Additionally, we employed in vivo models and conducted analyses on patient databases to ensure the translational relevance of our results. We revealed SEMA3F as a promoter of invasion during the DCIS-to-invasive ductal carcinoma transition in breast cancer (BC) through the action of NRP1 and NRP2. In epithelial cells, SEMA3F activates epithelialmesenchymal transition, whereas it promotes extracellular matrix degradation and basal membrane and myoepithelial cell layer breakdown. Together with our patient database data, these proof-of-concept results reveal new SEMA3F-mediated mechanisms occurring in the most common preinvasive BC lesion, DCIS, and represent potent and direct activation of its transition to invasion. Moreover, and of clinical and therapeutic relevance, the effects of SEMA3F can be blocked directly through its coreceptors, thus preventing invasion and keeping DCIS lesions in the preinvasive state.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2025

A multiscale model of the action of a capsid assembly modulator for the treatment of chronic hepatitis B

Chronic hepatitis B virus (HBV) infection is strongly associated with increased risk of liver cancer and cirrhosis. While existing treatments effectively inhibit the HBV life cycle, viral rebound frequently occurs following treatment interruption. Consequently, functional cure rates of chronic HBV infection remain low and there is increased interest in a novel treatment modality, capsid assembly modulators (CAMs). Here, we develop a multiscale mathematical model of CAM treatment in chronic HBV infection. By fitting the model to participant data from a phase I trial of the first-generation CAM vebicorvir, we estimate the drug’s dose-dependent effectiveness and identify the physiological mechanisms that drive the observed biphasic decline in HBV DNA and RNA, and mechanistic differences between HBeAg-positive and negative infection. Finally, we demonstrate analytically and numerically that the relative change of HBV RNA more accurately reflects the antiviral effectiveness of a CAM than the relative change in HBV DNA.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Acute total body ionizing gamma radiation induces long-term adverse effects and immediate changes in cardiac protein oxidative carbonylation in the rat

Radiation-induced heart disease presents a significant challenge in the event of an accidental radiation exposure as well as to cancer patients who receive acute doses of irradiation as part of radiation therapy. We utilized the spontaneously hypertensive Wistar-Kyoto rat model, previously shown to demonstrate drug-induced cardiomyopathy, to evaluate the acute and long-term effects of sub-lethal total body gamma irradiation at two, four, and fiftytwo weeks. We further examined irreversible oxidative protein carbonylation in the heart immediately following irradiation in the normotensive Wistar-Kyoto rat. Both males and females sustained weight loss and anemic conditions compared to untreated controls over a one-year period as reflected by reduced body weight and low red blood cell count. Increased inflammation was detected by elevated IL-6 serum levels selectively in males at four weeks. Serum cardiac troponin T and I analyses revealed signs of cardiomyopathy at earlier timepoints, but high variability was observed, especially at one year. Echocardiography at two weeks following 5.0Gy treatment revealed a significant decrease in cardiac output in females and a significant decrease in both diastolic and systolic volumes in males. Following 10.0Gy irradiation in the normotensive Wistar-Kyoto rat, the heart tissue showed an increase in total protein oxidative carbonylation accompanied by DNA damage indicated by an increase in γ-H2AX. Using proteomic analyses, we identified several novel proteins which showed a marked difference in carbonylation including those of mitochondrial origin and most notably, cardiac troponin T, one of the key proteins involved in cardiomyocyte contractility. Overall, we present findings of acute oxidative protein damage, DNA damage, cardiac troponin T carbonylation, and long-term cardiomyopathy in the irradiated animals.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

COVID-19 Evidence Accelerator: A parallel analysis to describe the use of Hydroxychloroquine with or without Azithromycin among hospitalized COVID-19 patients

Background: The COVID-19 pandemic remains a significant global threat. However, despite urgent need, there remains uncertainty surrounding best practices for pharmaceutical interventions to treat COVID-19. In particular, conflicting evidence has emerged surrounding the use of hydroxychloroquine and azithromycin, alone or in combination, for COVID-19. The COVID-19 Evidence Accelerator convened by the Reagan-Udall Foundation for the FDA, in collaboration with Friends of Cancer Research, assembled experts from the health systems research, regulatory science, data science, and epidemiology to participate in a large parallel analysis of different data sets to further explore the effectiveness of these treatments. Methods: Electronic health record (EHR) and claims data were extracted from seven separate databases. Parallel analyses were undertaken on data extracted from each source. Each analysis examined time to mortality in hospitalized patients treated with hydroxychloroquine, azithromycin, and the two in combination as compared to patients not treated with either drug. Cox proportional hazards models were used, and propensity score methods were undertaken to adjust for confounding. Frequencies of adverse events in each treatment group were also examined. Results: Neither hydroxychloroquine nor azithromycin, alone or in combination, were significantly associated with time to mortality among hospitalized COVID-19 patients. No treatment groups appeared to have an elevated risk of adverse events. Conclusion: Administration of hydroxychloroquine, azithromycin, and their combination appeared to have no effect on time to mortality in hospitalized COVID-19 patients. Continued research is needed to clarify best practices surrounding treatment of COVID-19.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib

Bruton’s tyrosine kinase (BTK) is the target of the therapeutic agent, Ibrutinib, that treats chronic lymphocyte leukemia (CLL), mantle cell lymphoma (MCL) and other B cell malignancies. Ibrutinib is a first in class, covalent BTK inhibitor that limits B-cell survival and proliferation. Designing new inhibitors of BTK has been an important objective for advancing development of improved therapeutic agents against cancer and autoimmune disorders. Based on the success of Ibrutinib, several second-generation irreversible BTK inhibitors have been developed that exhibit fewer off-target effects. However, the binding-mode and their interaction with Btk have not been experimentally determined and evaluated at atomic resolution. Here we determined the first crystal structure of the BTK kinase domain in complex with acalabrutinib. In addition, we report a structure of the BTK/tirabrutinib complex and compare these structures with previously solved structures. The structures provide insight in the superior selectivity reported for acalabrutinb and guide future BTK inhibitor development.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Ser 71 Phosphorylation Inhibits Actin-Binding of Profilin-1 and Its Apoptosis-Sensitizing Activity

The essential actin-binding factor profilin-1 (Pfn1) is a non-classical tumor suppressor with the abilities toboth inhibit cellular proliferation and augment chemotherapy-induced apoptosis. Besides actin, Pfn1 interacts with proteins harboring the poly-L-proline (PLP) motifs. Our recent work demonstrated that both nuclear localization and PLP-binding are required for tumor growth inhibition by Pfn1, and this is at least partially due to Pfn1 association with the PLP-containing ENL protein in the Super Elongation Complex (SEC) and the transcriptional inhibition of pro-cancer genes. In this paper, by identifying a phosphorylation event of Pfn1 at Ser 71 capable of inhibiting its actin-binding and nuclear export, we provide in vitro and in vivo evidence that chemotherapy-induced apoptotic sensitization by Pfn1 requires its cytoplasmic localization and actin-binding. With regard to tumor growth inhibition byPfn1, our data indicate a requirement for dynamic actin association and dissociation rendered by reversible Ser 71 phosphorylation and dephosphorylation. Furthermore, genetic and pharmacological experiments showed that Ser 71 of Pfn1 can be phosphorylated by protein kinase A (PKA). Taken together, our data provide novel mechanistic insights into the multifaceted anticancer activities of Pfn1 and how they are spatially-defined in the cell and differentially regulated by ligand-binding.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Heavy Ion Minibeam Therapy: Side Effects in Normal Brain

The purpose of this work was to investigate whether minibeam therapy with heavy ions might offer improvements of the therapeutic ratio for the treatment of human brain cancers. To assess neurotoxicity, we irradiated normal juvenile rats using 120 MeV lithium-7 ions at an absorbed integral dose of 20 Gy. Beams were configured either as a solid parallel circular beam or as an array of planar parallel minibeams having 300-micron width and 1-mm center-to-center spacing within a circular array. We followed animals for 6 months after treatment and utilized behavioral testing and immunohistochemical studies to investigate the resulting cognitive impairment and chronic pathologic changes. We found both solid-beam therapy and minibeam therapy to result in cognitive impairment compared with sham controls, with no apparent reduction in neurotoxicity using heavy ion minibeams instead of solid beams under the conditions of this study.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

Alterations in Progesterone Receptor Isoform Balance in Normal and Neoplastic Breast Cells Modulates the Stem Cell Population

To investigate the role of PR isoforms on the homeostasis of stem cells in the normal and neoplastic mammary gland, we used PRA and PRB transgenic mice and the T47D human breast cancer cell line and its derivatives, T47D YA and YB (manipulated to express only PRA or PRB, respectively). Flow cytometry and mammosphere assays revealed that in murine breast, overexpression of PRB leads to an increase in luminal and basal progenitor/stem cells. Ovariectomy had a negative impact on the luminal compartment and induced an increase in mammosphere-forming capacity in cells derived from WT and PRA mice only. Treatment with ICI 182,780 augmented the mammosphere-forming capacity of cells isolated from WT and PRA mice, whilst those from PRB remained unaltered. T47D YB cells showed an increase in the CD44+/CD24Low/- subpopulation; however, the number of tumorspheres did not vary relative to T47D and YA, even though they were larger, more irregular, and had increased clonogenic capacity. T47D and YA tumorspheres were modulated by estrogen/antiestrogens, whereas YB spheres remained unchanged in size and number. Our results show that alterations in PR isoform balance have an impact on normal and tumorigenic breast progenitor/stem cells and suggest a key role for the B isoform, with implications in response to antiestrogens.

stem cells↗

DOE OSTI2020

Imaging of Fibroblast Activation Protein Alpha Expression in a Preclinical Mouse Model of Glioma Using Positron Emission Tomography

Glioblastoma multiforme (GBM) is the most aggressive glioma of the primary central nervous system. Due to the lack of effective treatment options, the prognosis for patients remains bleak. Fibroblast activation protein alpha (FAP), a 170 kDa type II transmembrane serine protease was observed to be expressed on glioma cells and within the glioma tumor microenvironment. To understand the utility of targeting FAP in this tumor type, the immuno-PET radiopharmaceutical [ 89 Zr]Zr-Df-Bz-F19 mAb was prepared and Lindmo analysis was used for its in vitro evaluation using the U87MG cell line, which expresses FAP endogenously. Lindmo analysis revealed an association constant (K a ) of 10 -8 M -1 and an immunoreactivity of 52%. Biodistribution studies in U87MG tumor-bearing mice revealed increasing radiotracer retention in tumors over time, leading to average tumor-to-muscle ratios of 3.1, 7.3, 7.2, and 8.3 at 2, 24, 48 and 72 h, respectively. Small animal PET corroborated the biodistribution studies; tumor-to-muscle ratios at 2, 24, 48, and 72 h were 2.0, 5.0, 6.1 and 7.8, respectively. Autoradiography demonstrated accumulated activity throughout the interior of FAP + tumors, while sequential tumor sections stained positively for FAP expression. Conversely, FAP - tissues retained minimal radioactivity and were negative for FAP expression by immunohistochemistry. These results demonstrate FAP as a promising biomarker that may be exploited to diagnose and potentially treat GBM and other neuroepithelial cancers.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2021

An evaluation of prognostic factors, oncologic outcomes, and management for primary and recurrent squamous cell carcinoma of the vulva

Objective: To evaluate prognostic factors, outcomes, and management patterns of patients treated for squamous cell carcinoma of the vulva. Methods: One hundred sixty-four women were retrospectively identified with primary squamous cell carcinoma of the vulva treated at our institution between 1/1996–12/2018. Descriptive statistics were performed on patient, tumor, and treatment characteristics. The χ 2 tests and t-tests were used to compare categorical variables and continuous variables, respectively. Recurrence free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards. Results: Median follow-up was 52.5 months. Five-year RFS was 67.9%, 60.0%, 42.1%, and 20.0% for stage I–IV, respectively. Five-year DSS was 86.2%, 81.6%, 65.0%, and 42.9% for stage I–IV, respectively. On multivariate analysis, positive margins predicted overall RFS (hazard ratio [HR]=3.55; 95% confidence interval [CI]=1.18–10.73; p=0.025), while presence of lichen sclerosus on pathology (HR=2.78; 95% CI=1.30–5.91; p=0.008) predicted local RFS. OS was predicted by nodal involvement (HR=2.51; 95% CI=1.02–6.13; p=0.043) and positive margins (HR=5.19; 95% CI=2.03–13.26; p=0.001). Adjuvant radiotherapy significantly improved RFS (p=0.016) and DSS (p=0.012) in node-positive patients. Median survival after treatment of local, groin, and pelvic/distant recurrence was 52, 8, and 5 months, respectively. Conclusion: For primary treatment, more conservative surgical approaches can be considered with escalation of treatment in patients with concurrent precursor lesions, positive margins, and/or nodal involvement. Further studies are warranted to improve risk stratification in order to optimize treatment paradigms for vulvar cancer patients.

60 APPLIED LIFE SCIENCES↗

NASA NTRS2016

Team Update on North American Proton Facilities for Radiation Testing

In the wake of the closure of the Indiana University Cyclotron Facility (IUCF), this presentation provides an overview of the options for North American proton facilities. This includes those in use by the aerospace community as well as new additions from the cancer therapy regime. In addition, proton single event testing background is provided for understanding the criteria needed for these facilities for electronics testing.

Single event effects testing↗

NASA NTRS2016

Team Update on North American Proton Facilities for Radiation Testing

Proton cyclotrons↗

NASA NTRS2016

Team Update on North American Proton Facilities for Radiation Testing

Single event effects testing↗

NASA NTRS2016

Team Update on North American Proton Facilities for Radiation Testing

Cancer therapy↗

NASA NTRSDate not supplied

Assessing Long-Term Health (LTH) Outcomes in Astronauts

NASA has linked potential Long-Term Health (LTH) risks of astronauts to their spaceflight experience, including the effects of space radiation, microgravity, and stressors such as isolation, sleep deprivation, and stress. Therefore, assessing the LTH outcomes for astronauts exposed to these hazards becomes a critical investigation in ensuring any deleterious effects are minimal. Prior research conducted into LTH outcomes of astronauts has not revealed increases in non-accidental mortality rates when compared to the U.S. general population, analog healthy cohorts, and professional athletes. One study did report an increased incidence of non-fatal cardiovascular disease events (Hazard Ratio=2.41, 95% Confidence Interval 1.26 to 4.63). Additional evidence indicates that astronauts may have increases in incidences of melanoma, prostate, and hematologic cancers, though the former is consistent with rates observed among aircraft pilots and the latter two are likely caused by detection bias due to increased screening on former astronauts.

long term health↗

DOE OSTI2023

Preparation of 2D Polyaniline/MoO 3– x Superlattice Nanosheets via Intercalation-Induced Morphological Transformation for Efficient Chemodynamic Therapy

Organic intercalation of layered nanomaterials is an attractive strategy to fabricate organic/inorganic superlattices for a wide range of promising applications. However, the synthesis of 2D organic/inorganic superlattice nanosheets remains a big challenge. In this work, the preparation of 2D polyaniline/MoO 3–x (PANI/MoO 3–x ) superlattice nanosheets via intercalation-induced morphological transformation from MoO 3 nanobelts, as efficient Fenton-like reagents for chemodynamic therapy (CDT), is reported. Micrometer-long MoO 3 nanobelts are co-intercalated with Na + /H 2 O followed by the guest exchange with aniline monomer for in situ polymerization to obtain PANI/MoO 3–x nanosheets. Intriguingly, the PANI intercalation can induce the morphological transformation from long MoO 3 nanobelts to 2D PANI/MoO 3–x nanosheets along with the partial reduction of Mo 6+ to Mo 5+ , and generation of rich oxygen vacancies. More importantly, thanks to the PANI intercalation-induced activation, the PANI/MoO 3–x nanosheets exhibit excellent Fenton-like catalytic activity for generation of hydroxyl radical (·OH) by decomposing H 2 O 2 compared with the MoO 3 nanobelts. It is speculated that the good conductivity of PANI can facilitate electron transport during the Fenton-like reaction, thereby enhancing the efficiency of CDT. Thus, the polyvinylpyrrolidone-modified PANI/MoO 3–x nanosheets can function as Fenton-like reagents for highly efficient CDT to kill cancer cells and eradicate tumors.

2D materials↗

DOE OSTI2023

Extending Imaging Volume in Soft X‐Ray Tomography

Soft X‐ray tomography offers rapid imaging of whole, single cells with a few tens of nanometers spatial resolution without fixation or labeling. Herein, this technique is limited to specimens about 10 μm thick, such that applications of soft X‐ray tomography of large human cells or multicellular specimens are not possible. A theoretical and experimental framework for soft X‐ray tomography that enables extension of imaging volumes to 18 μm‐thick specimens is developed. This approach, based on long depth of field and half‐acquisition tomography, is easily applicable to microscopes equipped with a full‐rotation specimen stage. This opens opportunities for imaging large human cells, such as those commonly seen in cancer research, as well as cell‐to‐cell interactions, where two or more cells occupy the same imaging volume.

Ekman, Axel↗

DOE OSTI2024

Multihead Attention U‐Net for Magnetic Particle Imaging–Computed Tomography Image Segmentation

Magnetic particle imaging (MPI) is an emerging noninvasive molecular imaging modality with high sensitivity and specificity, exceptional linear quantitative ability, and potential for successful applications in clinical settings. Computed tomography (CT) is typically combined with the MPI image to obtain more anatomical information. Herein, a deep learning‐based approach for MPI‐CT image segmentation is presented. The dataset utilized in training the proposed deep learning model is obtained from a transgenic mouse model of breast cancer following administration of indocyanine green (ICG)‐conjugated superparamagnetic iron oxide nanoworms (NWs‐ICG) as the tracer. The NWs‐ICG particles progressively accumulate in tumors due to the enhanced permeability and retention (EPR) effect. The proposed deep learning model exploits the advantages of the multihead attention mechanism and the U‐Net model to perform segmentation on the MPI‐CT images, showing superb results. In addition, the model is characterized with a different number of attention heads to explore the optimal number for our custom MPI‐CT dataset.

Juhong, Aniwat↗