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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 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
NASA NTRS2004

The Effects of Protein Regulators on the Vascular Remodeling of Japanese Quail Chorioallantoic Membrane

Contributing to NASA s mission, the Microgravity Fluid Physics research program conducts experiments to promote space exploration and improvement of processes and products on Earth. One of the projects through this program deals with the affect of regulators on vascular remodeling and angiogenesis. This project is being led by Dr. Patricia Parsons-Wingerter. To perform the experiments, protein regulators are tested on the chorioallantoic membrane (CAM) of the Japanese quail embryos. The different types of regulators used can be broken down into two major groups of stimulators, and inhibitors. Stimulators increase the rate of blood vessel growth and inhibitors decrease of blood vessel growth. The specified regulator proteins include thrombospondin 1 (TSP-1) and a novel vessel tortuosity factor (TF), these are just the ones used in this specific experiment; other various protein regulators can also be used. The novel vessel tortuosity factor (TF) is a special kind of stimulator because it stimulates vessel tortuosity and curvature, rather than actual blood vessel growth. These regulators are being tested on Japanese quail embryos. The Japanese quail embryos naturally form a chorioallantoic membrane (CAM) from which blood flow, vascular remodeling, and angiogenesis can be observed. Chorioallantoic membranes are also easier to use because they are two dimensional when mounted onto a slide for examination. The analysis of the affect of the regulators on the CAM can be studied through PIVPROC; the program is used to analyze the altered blood flow in response to application of TF. Regulators are being thoroughly studied because cardiovascular alterations are the second highest, NASA-defined, risk categories in human space exploration. This research done on the quail is extending to even more projects that will be done on lab animals such as mice and also in human clinical studies like the diabetic retina. Not only will this research be beneficial to further space exploration, but it will also help life here on Earth. The higher understanding of the formation of blood vessels can also help further research in health problems such as diabetes and heart disease.

Deshpande, Arati↗
NASA NTRS2010

Mapping and Quantification of Vascular Branching in Plants, Animals and Humans by VESGEN Software

Humans face daunting challenges in the successful exploration and colonization of space, including adverse alterations in gravity and radiation. The Earth-determined biology of humans, animals and plants is significantly modified in such extraterrestrial environments. One physiological requirement shared by humans with larger plants and animals is a complex, highly branching vascular system that is dynamically responsive to cellular metabolism, immunological protection and specialized cellular/tissue function. The VESsel GENeration (VESGEN) Analysis has been developed as a mature beta version, pre-release research software for mapping and quantification of the fractal-based complexity of vascular branching. Alterations in vascular branching pattern can provide informative read-outs of altered vascular regulation. Originally developed for biomedical applications in angiogenesis, VESGEN 2D has provided novel insights into the cytokine, transgenic and therapeutic regulation of angiogenesis, lymphangiogenesis and other microvascular remodeling phenomena. Vascular trees, networks and tree-network composites are mapped and quantified. Applications include disease progression from clinical ophthalmic images of the human retina; experimental regulation of vascular remodeling in the mouse retina; avian and mouse coronary vasculature, and other experimental models in vivo. We envision that altered branching in the leaves of plants studied on ISS such as Arabidopsis thaliana cans also be analyzed.

Parsons-Wingerter, Patricia A.↗
NASA NTRS2010

Mapping and Quantification of Vascular Branching in Plants, Animals and Humans by VESGEN Software

Humans face daunting challenges in the successful exploration and colonization of space, including adverse alterations in gravity and radiation. The Earth-determined biology of plants, animals and humans is significantly modified in such extraterrestrial environments. One physiological requirement shared by larger plants and animals with humans is a complex, highly branching vascular system that is dynamically responsive to cellular metabolism, immunological protection and specialized cellular/tissue function. VESsel GENeration (VESGEN) Analysis has been developed as a mature beta version, pre-release research software for mapping and quantification of the fractal-based complexity of vascular branching. Alterations in vascular branching pattern can provide informative read-outs of altered vascular regulation. Originally developed for biomedical applications in angiogenesis, VESGEN 2D has provided novel insights into the cytokine, transgenic and therapeutic regulation of angiogenesis, lymphangiogenesis and other microvascular remodeling phenomena. Vascular trees, networks and tree-network composites are mapped and quantified. Applications include disease progression from clinical ophthalmic images of the human retina; experimental regulation of vascular remodeling in the mouse retina; avian and mouse coronary vasculature, and other experimental models in vivo. We envision that altered branching in the leaves of plants studied on ISS such as Arabidopsis thaliana cans also be analyzed.

Parsons-Wingerter, P. A.↗
DOE OSTI2019

A novel role mediated by adenoviral E1A in suppressing cancer through modulating decorin

Oncolytic adenovirus is an emerging alternative to current therapeutics. The adenoviral E1A, the first protein expressed upon oncolytic adenoviral infection, has been identified as an antitumor agent, but the mechanisms of its tumor inhibition ability are unclear enough. Decorin is ubiquitous in the extracellular matrix (ECM), which regulates multiple functions through interaction with ECM. Here, we intended to explore the effects of adenoviral E1A on the tumor extracellular matrix during gene therapy. We demonstrated that reduced decorin expression was found in patients with lung cancer. The adenoviral E1A or a mutant adenoviral E1A with Rb-binding ability absent (E1A 30–60aa, 120–127aa deletion) could increase the expression of decorin and down-regulate VEGF, two members of tumor ECM, involved in both vasculogenesis and angiogenesis. E1A/mE1A-mediated suppressing the migration and invasion ability of tumor cells was depended on decorin. E1A interacted with decorin directly and induced the proteasomal degradation of VEGF. In addition, E1A or mE1A can inhibit tumor growth in a subcutaneous lung cancer xenograft model. It suggested that decorin might be a crucial mediator among ECM components for adenoviral E1A-mediated antitumor activities. These studies on adenovirus E1A provide a new mechanism for the emerging therapies of tumor gene therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Antineoplastic activity of Salmonella Typhimurium outer membrane nanovesicles

Highlights: • ST-OMVs is a promising antitumor monotherapy or as an adjuvant to chemotherapies. • ST-OMVs downregulated Ki-67 and upregulated CD49b immune-expression. • ST-OMVs downregulated angiogenesis by inhibiting VEGF gene expression. • ST-OMVs increased tumor cells apoptosis and autophagy (increased caspase-3and Beclin1). Nano-sized Gram-negative bacterial outer membrane vesicles possess unique structural and immunostimulatory effects that could be exploited to regress tumors by alerting the host immune system and reversing the immunosuppressive tumor microenvironment. The current study was conducted to investigate the antitumor activity of the outer membrane vesicles (ST-OMVs) of Salmonella Typhimurium ATCC 14028, in vitro in human colorectal carcinoma (HTC116), breast cancer (MCF-7), and hepatocellular carcinoma (HepG2) cell lines and in vivo in Ehrlich solid carcinoma-bearing mice model either as a mono-immunotherapy or as an adjuvant to a commonly used conventional chemotherapy. In addition, we investigated the safety of ST-OMVs. Adult Swiss albino female mice with transplanted Ehrlich solid carcinoma were treated with either ST-OMVs, paclitaxel or a combination of both. Tumor volume, growth inhibition rate, quantitative RT-PCR of Bax and VEGF genes expression, histopathology and immune-expression of caspase-3, Beclin-1, CD49b and Ki-67 were all analyzed. Our results showed that ST-OMVs significantly decreased tumor volume, significantly increased tumor growth inhibition rate, up-regulated the immunohistochemical expression of caspase-3, Beclin-1, and CD49b (enhanced recruitment of NK cells). Furthermore, ST-OMVs down-regulated the expression of Ki-67, increased Bax gene expression and decreased VEGF gene expression as detected by qRT-PCR analysis. Histologically, ST-OMVs promoted apoptosis, decreased tumor invasion and mitotic activities. Moreover, ST-OMVs showed a remarkable cytotoxic activity in various investigated in vitro cancer cell lines. Our findings demonstrate potential antitumor activity of ST-OMVs that might be used as a promising safe antitumor immunotherapy or an adjuvant to conventional chemotherapeutic drugs, resolving some of their problems.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

LncRNA embryonic stem cells expressed 1 (Lncenc1) is identified as a novel regulator in neuropathic pain by interacting with EZH2 and downregulating the expression of Bai1 in mouse microglia

LncRNA embryonic stem cells expressed 1 (Lncenc1), named after its high expression in naïve embryonic stem cells (nESCs), has been rarely studied in almost all pathological processes. Evidences suggest that Lncenc1 is likely to work in the form of RNA-protein complex. Here, we found that Lncenc1 in dorsal root ganglion (DRG) was significantly upregulated in response to mouse nerve injury caused by partial sciatic nerve ligation (pSNL). Overexpression of Lncenc1 mediated by adenoviral expression vector promoted the activation of microglia and the production of inflammatory cytokines including TNF-α, IL-1β and MCP-1. In contrast, knockdown of Lncenc1 suppressed activation of microglia and production of inflammatory cytokines. In the mechanism exploration, we found that Lncenc1 could bind with the RNA binding protein (RBP) enhancer of zeste homologue 2 (EZH2), an identified contributor in microglial activation and neuropathic pain. Lncenc1 interacted with EZH2 and downregulated the expression of brain-specific angiogenesis inhibitor 1 (BAI1). Either inhibition of EZH2 or overexpression of BAI1 could reverse the effects of Lncenc1 overexpression on microglial activation and neuroinflammation. Finally, the Lncenc1-siRNA was intrathecally injected into pSNL mice, and its effects on neuropathic pain were evaluated. Knockdown of Lncenc1 attenuated the development and maintenance of mechanical and thermal hyperalgesia of pSNL mice, accompanied by an increase in BAI1 expression and decrease in inflammatory cytokines. In conclusion, Lncenc1 contributes to neuropathic pain by interacting with EZH2 and downregulating the BAI1 gene in mouse microglia.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

The CAM assay in the study of the metastatic process

Among the in vivo experimental models, the chick embryo chorioallantoic membrane (CAM) has been routinely used to implant several malignant cell lines or tumor tissues to study their angiogenic and metastatic capability. Since the chick embryo is naturally immunodeficient, the CAM can support the engraftment of tumor cells, and their growth therein can faithfully recapitulate most of the characteristics of the carcinogenic process including: growth, invasion, angiogenesis and colonization of distant tissues. This review article is focused on the discussion of the more recent literature data concerning the use of the CAM to investigate the metastatic process.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

A dehydrated, aseptically-processed human amnion/chorion allograft accelerates healing in a delayed murine excisional wound model

Since chronic, non-healing wounds represent an increasing source of economic and temporal burden for patients who suffer from them and healthcare professionals that treat them, therapeutic modalities that promote closure of delayed and non-healing wounds are of utmost importance. Recent clinical results of allografts derived from amnion and chorion placental layers encourage further investigation of the mechanisms underlying clinical efficacy of these products for treatment of wounds. Here, we utilized a diabetic murine splinted excisional wound model to investigate the effects of a dehydrated human amnion/chorion-derived allograft (dHACA) on delayed wound healing, as well as the effects of dehydrated allograft derived solely from amnion tissue of the same donor. We examined wound healing by histological endpoint analysis, and we assessed other parameters relevant to functional wound healing in the wound bed including angiogenesis, macrophage phenotypes, proliferative activity, and gene expression. Herein we demonstrate that application of dHACA to a murine diabetic model of delayed wound progression results in better macroscale wound resolution outcomes, including rate of closure, compared to unaided wound progression, while dehydrated human amnion allograft (dHAA) fails to improve outcomes. Improved gross wound resolution observed with dHACA was accompanied by increased granulation tissue formation, proliferation and vascular ingrowth observed in the wound bed, early macrophage polarization towards anti-inflammatory phenotypes, and downregulation of pro-fibrotic gene expression. Overall, our data suggest that improvements in the rates of delayed wound closure observed from combined amnion/chorion allografts are associated with modulation of critical cellular and tissue processes commonly found to be dysregulated in delayed healing wounds, including proliferation, vascularization, inflammation, and re-epithelialization.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

NF-κB activation in retinal microglia is involved in the inflammatory and neovascularization signaling in laser-induced choroidal neovascularization in mice

Highlights: • IMD0354 treatment reduced the microglia infiltration, fluorescein leakage and size of the laser CNV spots. • IKK2 inhibition suppressed phospho-IκBα, VEGF-A, and COX-2 in the Laser CNV mouse eyes. • IMD-0354 treated eyes demonstrated reduced microglial migration to the laser injury site. • In vitro, IKK2 inhibition reduced NF-κB activation, COX-2, Actin-F presence, and the microglia cells' migration capacity. To evaluate Nuclear Factor NF-κB (NF-κB) signaling on microglia activation, migration, and angiogenesis in laser-induced choroidal neovascularization (CNV).

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Chorioallantoic membrane vascularization. A meta-analysis

The CAM is a widely used experimental assay to study angiogenesis, wound healing, tumor growth and metastatic process. In this study, we have analyzed and compared the existent literature data concerning the growth of the CAM. Moreover, we have analyzed the data concerning the development of the vascular system and the expression of the most important pro-angiogenic and anti-angiogenic factors. The availability of these data and their comparative evaluation allow to better analyze the experimental data concerning the testing of different pro-angiogenic and anti-angiogenic molecules, as well as biomaterials in the CAM assay. Moreover, the dynamic of the angiogenic response to different tumor cell lines and or tumor bioptic specimens, may be also better evaluated and estimated.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Competing endogenous RNA network associated with oxygen-induced retinopathy: Expression of the network and identification of the MALAT1/miR-124–3p/EGR1 regulatory axis

Retinopathy of prematurity (ROP) is a severe retinal dysfunction in prematurely born babies. The relationship between non-coding RNAs and retinopathy of prematurity (ROP) remain unclear. Microarray analysis of lncRNAs, miRNAs, and mRNAs was conducted in a mouse model of ROP. A competing endogenous RNA (ceRNA) network was constructed. The relationship among MALAT1, miR-124–3p, and Early growth response protein 1 (EGR1) was assessed in hypoxia-induced primary human umbilical vein endothelial cells (HUVECs) and ROP mouse model. In the study, we found 2252 lncRNAs, 1239 mRNAs, and 36 miRNAs were differentially regulated. ceRNA network consisting of 21 lncRNAs, 10 miRNAs, and 19 mRNAs was established. Of the most down-regulated miRNAs, miR-124–3p was selected for additional study. miR-124–3p ceased the migration and proliferation of primary HUVECs in hypoxic conditions, and directly suppressed EGR1. Additionally, MALAT1 directly sponged miR-124–3p. Knockdown of MALAT1 decreased EGR1 expression and inhibited the migration and proliferation of primary HUVECs in hypoxia. Furthermore, these changes were rescued by depletion of miR-124–3p. In vivo, intravitreal injection of miR-124–3p, shMALAT1 decreased EGR1 expression and markedly suppressed retinal neovascularization in OIR models. Intravitreal injection of shMALAT1 and miR-124–3p antagomir at the same time can promote retinal neovascularization, which reversed the suppression of retinal neovascularization functioned by shMALAT1. In conclusion, the expression profiles of lncRNAs and miRNAs and the ceRNA network in a mouse model of ROP may be indicative of the underlying mechanisms of retinal angiogenesis and neural activity. The MALAT1/miR-124–3p/EGR1 regulatory axis is partly responsible for retinal neovascularization, which may provide a novel theoretical basis for the pathogenesis of ROP.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Substrate stiffness modulates endothelial cell function via the YAP-Dll4-Notch1 pathway

Highlights: • Soft stiffness increases Dll4 expression in endothelial cells via YAP suppression. • Soft substrate-induced Dll4-Notch1 signaling is facilitated by VEGF stimulation. • Elevated Dll4-Notch1 signaling contributes to the regulation of VEGFRs expression. • Substrate stiffness modulates gene expression linked to endothelial cell function. Endothelial cells adapt their functions as a consequence of sensing extracellular substrate stiffness; these alterations allow them to maintain their vascular structure and function. Substrate stiffness-mediated yes-associated protein 1 (YAP) activation plays an important role in mechano-transduction and pro-angiogenic phenotype of endothelial cells, and Delta-like ligand 4 (Dll4)-Notch1 signaling is closely related to angiogenesis; however, the impact of substrate stiffness-mediated interrelation of these pathways on endothelial cell functions remains elusive. We confirmed that endothelial cells on softer substrates not only elongate cellular aspects but also attenuate YAP activation compared to cells on stiffer substrates. Endothelial cells on softer substrates also upregulate the vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 mRNA expression that is enhanced by VEGF stimulation. We determined that endothelial cells on softer substrates increased Dll4 expression, but not Notch1 expression, via YAP signaling. Moreover, endothelial cells on soft substrates induced not only VEGFRs upregulation but also suppression of pro-inflammatory interleukin-6 and plasminogen activator inhibitor-1 mRNA expression and the facilitation of anti-coagulant thrombomodulin and pro-coagulant tissue factor mRNA expression. Our results suggest that endothelial cells activate the YAP-Dll4-Notch signaling pathway in response to substrate stiffness and dictate cellular function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Development of a Novel Humanized Monoclonal Antibody to Secreted Frizzled-Related Protein-2 That Inhibits Triple-Negative Breast Cancer and Angiosarcoma Growth In Vivo

Background: We previously reported that secreted frizzled-related protein-2 (SFRP2) is expressed in a variety of tumors, including sarcoma and breast carcinoma, and stimulates angiogenesis and inhibits tumor apoptosis. Therefore, we hypothesized that a humanized SFRP2 monoclonal antibody (hSFRP2 mAb) would inhibit tumor growth. Methods: The lead hSFRP2 antibody was tested against a cohort of 22 healthy donors using a time course T-cell assay to determine the relative risk of immunogenicity. To determine hSFRP2 mAb efficacy, nude mice were subcutaneously injected with SVR angiosarcoma cells and treated with hSFRP2 mAb 4 mg/kg intravenously every 3 days for 3 weeks. We then injected Hs578T triple-negative breast cells into the mammary fat pad of nude mice and treated for 40 days. Control mice received an immunoglobulin (Ig) G1 control. The SVR and Hs578T tumors were then stained using a TUNEL assay to detect apoptosis. Results: Immunogenicity testing of hSFRP2 mAb did not induce proliferative responses using a simulation index (SI) ≥ 2.0 (p < 0.05) threshold in any of the healthy donors. SVR angiosarcoma tumor growth was inhibited in vivo, evidenced by significant tumor volume reduction in the hSFRP2 mAb-treated group, compared with controls (n = 10, p < 0.001). Likewise, Hs578T triple-negative breast tumors were smaller in the hSFRP2 mAb-treated group compared with controls (n = 10, p < 0.001). The hSFRP2 mAb treatment correlated with an increase in tumor cell apoptosis (n = 11, p < 0.05). Importantly, hSFRP2 mAb treatment was not associated with any weight loss or lethargy. Conclusion: We present a novel hSFRP2 mAb with therapeutic potential in breast cancer and sarcoma that has no effect on immunogenicity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

MicroRNAs in laser-induced choroidal neovascularization in mice and rats: their expression and potential therapeutic targets

Choroidal neovascularization characterizes wet age-related macular degeneration. Choroidal neovascularization formation involves a primarily angiogenic process that is combined with both inflammation and proteolysis. A primary cause of choroidal neovascularization pathogenesis is alterations in pro- and anti-angiogenic factors derived from the retinal pigment epithelium, with vascular endothelium growth factor being mainly responsible for both clinical and experimental choroidal neovascularization. MicroRNAs (miRNAs) which are short, non-coding, endogenous RNA molecules have a major role in regulating various pathological processes, including inflammation and angiogenesis. A review of recent studies with the mouse laser-induced choroidal neovascularization model has shown alterations in miRNA expression in choroidal neovascularization tissues and could be potential therapeutic targets for wet age-related macular degeneration. Upregulation of miR-505 (days 1 and 3 post-laser), miR-155 (day 14) occurred in retina; miR-342-5p (days 3 and 7), miR-126-3p (day 14) in choroid; miR-23a, miR-24, miR-27a (day 7) in retina/choroid; miR-505 (days 1 and 3) in retinal pigment epithelium/choroid; downregulation of miR-155 (days 1 and 3), miR-29a, miR-29b, miR-29c (day 5), miR-93 (day 14), miR-126 (day 14) occurred in retinal pigment epithelium/choroid. Therapies using miRNA mimics or inhibitors were found to decrease choroidal neovascularization lesions. Choroidal neovascularization development was reduced by overexpression of miR-155, miR-188-5p, miR-(5,B,7), miR-126-3p, miR-342-5p, miR-93, miR-126, miR-195a-3p, miR24, miR-21, miR-31, miR-150, and miR-184, or suppression of miR-505, miR-126-3p, miR155, and miR-23/27. Further studies are warranted to determine miRNA expression in mouse laser-induced choroidal neovascularization models in order to validate and extend the reported findings. Important experimental variables need to be standardized; these include the strain and age of animals, gender, number and position of laser burns to the eye, laser parameters to induce choroidal neovascularization lesions including wavelength, power, spot size, and duration.

therapeutic targets↗
DOE OSTI2021

Development of an optimized and scalable method for isolation of umbilical cord blood-derived small extracellular vesicles for future clinical use

Abstract Extracellular vesicles (EV) are a promising therapeutic tool in regenerative medicine. These particles were shown to accelerate wound healing, through delivery of regenerative mediators, such as microRNAs. Herein we describe an optimized and upscalable process for the isolation of EV smaller than 200 nm (sEV), secreted by umbilical cord blood mononuclear cells (UCB-MNC) under ischemic conditions and propose quality control thresholds for the isolated vesicles, based on the thorough characterization of their protein, lipid and RNA content. Ultrafiltration and size exclusion chromatography (UF/SEC) optimized methodology proved superior to traditional ultracentrifugation (UC), regarding production time, standardization, scalability, and vesicle yield. Using UF/SEC, we were able to recover approximately 400 times more sEV per mL of media than with UC, and upscaling this process further increases EV yield by about 3-fold. UF/SEC-isolated sEV display many of the sEV/exosomes classical markers and are enriched in molecules with anti-inflammatory and regenerative capacity, such as hemopexin and miR-150. Accordingly, treatment with sEV promotes angiogenesis and extracellular matrix remodeling, in vitro. In vivo, UCB-MNC-sEV significantly accelerate skin regeneration in a mouse model of delayed wound healing. The proposed isolation protocol constitutes a significant improvement compared to UC, the gold-standard in the field. Isolated sEV maintain their regenerative properties, whereas downstream contaminants are minimized. The use of UF/SEC allows for the standardization and upscalability required for mass production of sEV to be used in a clinical setting.

Cardoso, Renato M. S.↗
DOE OSTI2025

Cohort-based pan-cancer analysis and experimental studies reveal ISG15 gene as a novel biomarker for prognosis and immunotherapy efficacy prediction

Abstract ISG15, an interferon-stimulated ubiquitin-like protein, plays a multifaceted role in tumorigenesis and immune regulation. This study comprehensively evaluates ISG15 as a prognostic biomarker and predictor of immunotherapy response through pan-cancer bioinformatics analysis and experimental validation. By integrating multiomics data from TCGA, GEO, and clinical cohorts, we found that ISG15 is significantly overexpressed in multiple cancers and generally correlates with poor prognosis. Elevated ISG15 expression is associated with increased immune checkpoint gene expression, particularly PD-L1, and immune infiltration, notably M2-like tumor-associated macrophages. Immunohistochemistry and multiplexed immunofluorescence confirmed a strong positive correlation between ISG15, PD-L1, and M2-TAM infiltration in lung and gastric cancer samples. Functional analysis at the single-cell level revealed significant associations between ISG15 and tumor proliferation, angiogenesis, and immune suppression. Immunotherapy cohort analysis demonstrated that tumors with high ISG15 expression responded favorably to PD-L1 inhibitors but exhibited resistance to CTLA-4 blockade, findings further validated in lung cancer patients receiving anti-PD-1 therapy. These results suggest that ISG15 is a promising biomarker for prognosis and immunotherapy response prediction across cancers. Its integration into clinical decision-making may enhance personalized treatment strategies, improve immunotherapy outcomes, and provide new insights into the tumor immune microenvironment, cancer progression, and potential therapeutic targets for future drug development.

Immunology↗
DOE OSTI2024

Vascular endothelial growth factor receptor-1 (FLT1) interactions with amyloid-beta in Alzheimer’s disease: A putative biomarker of amyloid-induced vascular damage

We have identified FLT1 as a protein that changes during Alzheimer's disease (AD) whereby higher brain protein levels are associated with more amyloid, more tau, and faster longitudinal cognitive decline. Given FLT1's role in angiogenesis and immune activation, we hypothesized that FLT1 is upregulated in response to amyloid pathology, driving a vascular-immune cascade resulting in neurodegeneration and cognitive decline. We sought to determine (1) if in vivo FLT1 levels (CSF and plasma) associate with biomarkers of AD neuropathology or differ between diagnostic staging in an aged cohort enriched for early disease, and (2) whether FLT1 expression interacts with amyloid on downstream outcomes, such as phosphorylated tau levels and cognitive performance. Additionally, we sought to replicate FLT1 interactions in the brain. The results showed that higher levels of FLT1 in CSF and post-mortem brain tissue related to increased tau, particularly among amyloid positive individuals. These analyses help clarify the potential utility of FLT1 as a biomarker among individuals with evidence of brain amyloidosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Single cell RNA sequencing reveals shifts in cell maturity and function of endogenous and infiltrating cell types in response to acute intervertebral disc injury

Intervertebral disc (IVD) degeneration contributes to disabling back pain. Degeneration can be initiated by injury and progressively leads to an irreversible loss of cells and function. IVD function restoration through cell replacement therapies have had limited success due to knowledge gaps in the critical cell populations important for repair. Here, in this study, we used single cell RNA sequencing to identify the transcriptional changes of IVD resident and infiltrating cell populations from Control and Injured coccygeal IVDs extracted from 12-week-old female C57BL/6J mice 7 days post injury. Clustering, gene ontology, and pseudotime trajectory analyses determined transcriptomic divergences with injury, flow cytometry identified they types of infiltrating immune cells, and immunofluorescence was utilized to define mesenchymal stem cell (MSC) localization. We identified 11 distinct clusters that included IVD, immune, vascular cells, and MSCs. Differential gene expression analysis determined that Outer Annulus Fibrosus, Neutrophils, Saa2-High MSCs, Macrophages, and Krt18 + Nucleus Pulposus (NP) cells were the major drivers of transcriptomic differences between Control and Injured cells. Gene ontology revealed that the most upregulated biological pathways were angiogenesis and T cell-related while wound healing and ECM regulation were downregulated. Pseudotime trajectory analyses revealed that IVD injury directed cells towards increased differentiation in all clusters, except for Krt18 + NP cells which remained in a less mature cell state. Saa2-High and Grem1-High MSCs populations shifted towards more differentiated IVD cells profiles with injury and localized distinctly within the IVD. This study revealed novel MSC populations with the potential to be leveraged for future IVD repair studies.

Cartilage↗