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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 325 records · Page 18
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Developmental Ethanol Exposure Impacts Purkinje Cells but Not Microglia in the Young Adult Cerebellum

Fetal alcohol spectrum disorders (FASD) caused by developmental ethanol exposure lead to cerebellar impairments, including motor problems, decreased cerebellar weight, and cell death. Alterations in the sole output of the cerebellar cortex, Purkinje cells, and central nervous system immune cells, microglia, have been reported in animal models of FASD. To determine how developmental ethanol exposure affects adult cerebellar microglia and Purkinje cells, we used a human third-trimester binge exposure model in which mice received ethanol or saline from postnatal (P) days 4–9. In adolescence, cerebellar cranial windows were implanted and mice were aged to young adulthood for examination of microglia and Purkinje cells in vivo with two-photon imaging or in fixed tissue. Ethanol had no effect on microglia density, morphology, dynamics, or injury response. However, Purkinje cell linear frequency was reduced by ethanol. Microglia–Purkinje cell interactions in the Purkinje Cell Layer were altered in females compared to males. Overall, developmental ethanol exposure had few effects on cerebellar microglia in young adulthood and Purkinje cells appeared to be more susceptible to its effects.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Oxidation of p-[125I]Iodobenzoic Acid and p-[211At]Astatobenzoic Acid Derivatives and Evaluation In Vivo

The alpha particle-emitting radionuclide astatine-211 (211At) is of interest for targeted radiotherapy; however, low in vivo stability of many 211At-labeled cancer-targeting molecules has limited its potential. As an alternative labeling method, we evaluated whether a specific type of astatinated aryl compound that has the At atom in a higher oxidation state might be stable to in vivo deastatination. In the research effort, para-iodobenzoic acid methyl ester and dPEG4-amino acid methyl ester derivatives were prepared as HPLC standards. The corresponding para-stannylbenzoic acid derivatives were also prepared and labeled with 125I and 211At. Oxidization of the [125I]iodo- and [211At]astato-benzamidyl-dPEG4-acid methyl ester derivatives provided materials for in vivo evaluation. A biodistribution was conducted in mice with coinjected oxidized 125I- and 211At-labeled compounds. The oxidized radioiodinated derivative was stable to in vivo deiodination, but unfortunately the oxidized [211At]astatinated benzamide derivative was found to be unstable under the conditions of isolation by radio-HPLC (post animal injection). Another biodistribution study in mice evaluated the tissue concentrations of coinjected [211At]NaAtO3 and [125I]NaIO3. Comparison of the tissue concentrations of the isolated material from the oxidized [211At]benzamide derivative with those of [211At]astatate indicated the species obtained after isolation was likely [211At]astatate.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Characterization of Humanized Mouse Model of Organophosphate Poisoning and Detection of Countermeasures via MALDI-MSI

Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research models have serum carboxylesterase, which contributes to animals’ resistance to OP poisoning. Historically, guinea pigs have been used for this research; however, a novel genetically modified mouse strain (KIKO) was developed with nonfunctional serum carboxylase (Es1 KO) and an altered acetylcholinesterase (AChE) gene, which expresses the amino acid sequence of the human form of the same protein (AChE KI). KIKO mice were injected with 1xLD50 of an OP nerve agent or vehicle control with or without atropine. After one to three minutes, animals were injected with 35 mg/kg of the currently fielded Reactivator countermeasure for OP poisoning. Postmortem brains were imaged on a Bruker RapifleX ToF/ToF instrument. Data confirmed the presence of increased acetylcholine in OP-exposed animals, regardless of treatment or atropine status. More interestingly, we detected a small amount of Reactivator within the brain of both exposed and unexposed animals; it is currently debated if reactivators can cross the blood–brain barrier. Further, we were able to simultaneously image acetylcholine, the primary affected neurotransmitter, as well as determine the location of both Reactivator and acetylcholine in the brain. This study, which utilized sensitive MALDI-MSI methods, characterized KIKO mice as a functional model for OP countermeasure development.

2-PAM↗
DOE OSTI2024

X-ray Fluorescence Microscopy to Develop Elemental Classifiers and Investigate Elemental Signatures in BALB/c Mouse Intestine a Week after Exposure to 8 Gy of Gamma Rays

Iron redistribution in the intestine after total body irradiation is an established phenomenon. However, in the literature, there are no reports about the use of X-ray fluorescence microscopy or equivalent techniques to generate semi-quantitative 2D maps of iron in sectioned intestine samples from irradiated mice. In this work, we used X-ray fluorescence microscopy (XFM) to map the elemental content of iron as well as phosphorus, sulfur, calcium, copper and zinc in tissue sections of the small intestine from eight-week-old BALB/c male mice that developed gastrointestinal acute radiation syndrome (GI-ARS) in response to exposure to 8 Gray of gamma rays. Seven days after irradiation, we found that the majority of the iron is localized as hot spots in the intercellular regions of the area surrounding crypts and stretching between the outer perimeter of the intestine and the surface cell layer of villi. In addition, this study represents our current efforts to develop elemental cell classifiers that could be used for the automated generation of regions of interest for analyses of X-ray fluorescence maps. Once developed, such a tool will be instrumental for studies of effects of radiation and other toxicants on the elemental content in cells and tissues. While XFM studies cannot be conducted on living organisms, it is possible to envision future scenarios where XFM imaging of single cells sloughed from the human (or rodent) intestine could be used to follow up on the progression of GI-ARS.

X-ray fluorescence microscopy↗
DOE OSTI2022

Heavy-Ion-Induced Lung Tumors: Dose- & LET-Dependence

There is a limited published literature reporting dose-dependent data for in vivo tumorigenesis prevalence in different organs of various rodent models after exposure to low, single doses of charged particle beams. The goal of this study is to reduce uncertainties in estimating particle-radiation-induced risk of lung tumorigenesis for manned travel into deep space by improving our understanding of the high-LET-dependent dose-response from exposure to individual ion beams after low particle doses (0.03 - 0.80 Gy). Female CB6F1 mice were irradiated with low single doses of either oxygen, silicon, titanium, or iron ions at various energies to cover a range of dose-averaged LET values from 0.2 - 193 keV/µm, using 137Cs γ-rays as the reference radiation. Sham-treated controls were included in each individual experiment totally 398 animals across the 5 studies reported. Based on power calculations, between 40 - 156 mice were included in each of the treatment groups. Tumor prevalence at 16 months after radiation exposure was determined and compared to the age-matched, sham-treated animals. Results indicate that lung tumor prevalence is non-linear as a function of dose with suggestions of threshold doses depending on the LET of the beams. Histopathological evaluations of the tumors showed that the majority of tumors were benign bronchioloalveolar adenomas with occasional carcinomas or lymphosarcomas which may have resulted from metastases from other sites.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Development of CD46 targeted alpha theranostics in prostate cancer using 134 Ce/ 225 Ac-Macropa-PEG 4 -YS5

Rationale: 225 Ac, a long-lived α-emitter with a half-life of 9.92 days, has garnered significant attention as a therapeutic radionuclide when coupled with monoclonal antibodies and other targeting vectors. Nevertheless, its clinical utility has been hampered by potential off-target toxicity, a lack of optimized chelators for 225 Ac, and limitations in radiolabeling methods. In a prior study evaluating the effectiveness of CD46-targeted radioimmunotherapy, we found great therapeutic efficacy but also significant toxicity at higher doses. To address these challenges, we have developed a radioimmunoconjugate called 225 Ac-Macropa-PEG 4 -YS5, incorporating a stable PEGylated linker to maximize tumoral uptake and increase tumor-to-background ratios. Our research demonstrates that this conjugate exhibits greater anti-tumor efficacy while minimizing toxicity in prostate cancer 22Rv1 tumors. Methods: We synthesized Macropa.NCS and Macropa-PEG 4/8 -TFP esters and prepared Macropa-PEG 0/4/8 -YS5 (with nearly ~1:1 ratio of macropa chelator to antibody YS5) as well as DOTA-YS5 conjugates. These conjugates were then radiolabeled with 225 Ac in a 2 M NH 4 OAc solution at 30 °C, followed by purification using YM30K centrifugal purification. Subsequently, we conducted biodistribution studies and evaluated antitumor activity in nude mice (nu/nu) bearing prostate 22Rv1 xenografts in both single-dose and fractionated dosing studies. Micro-PET imaging studies were performed with 134 Ce-Macropa-PEG 0/4/8 -YS5 in 22Rv1 xenografts for 7 days. Toxicity studies were also performed in healthy athymic nude mice. Results: As expected, we achieved a >95% radiochemical yield when labeling Macropa-PEG 0/4/8 -YS5 with 225 Ac, regardless of the chelator ratios (ranging from 1 to 7.76 per YS5 antibody). The isolated yield exceeded 60% after purification. Such high conversions were not observed with the DOTA-YS5 conjugate, even at a higher ratio of 8.5 chelators per antibody (RCY of 83%, an isolated yield of 40%). Biodistribution analysis at 7 days post-injection revealed higher tumor uptake for the 225 Ac-Macropa-PEG 4 -YS5 (82.82 ± 38.27 %ID/g) compared to other conjugates, namely 225 Ac-Macropa-PEG 0/8 -YS5 (38.2 ± 14.4/36.39 ± 12.4 %ID/g) and 225 Ac-DOTA-YS5 (29.35 ± 7.76 %ID/g). The PET Imaging of 134 Ce-Macropa-PEG 0/4/8 -YS5 conjugates resulted in a high tumor uptake, and tumor to background ratios. In terms of antitumor activity, 225 Ac-Macropa-PEG 4 -YS5 exhibited a substantial response, leading to prolonged survival compared to 225 Ac-DOTA-YS5, particularly when administered at 4.625 kBq doses, in single or fractionated dose regimens. Chronic toxicity studies observed mild to moderate renal toxicity at 4.625 and 9.25 kBq doses. Conclusions: Our study highlights the promise of 225 Ac-Macropa-PEG 4 -YS5 for targeted alpha particle therapy. The 225 Ac-Macropa-PEG 4 -YS5 conjugate demonstrates improved biodistribution, reduced off-target binding, and enhanced therapeutic efficacy, particularly at lower doses, compared to 225 Ac-DOTA-YS5. Incorporating theranostic 134 Ce PET imaging further enhances the versatility of macropa-PEG conjugates, offering a more effective and safer approach to cancer treatment. Overall, this methodology has a high potential for broader clinical applications.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Microbiota functional activity biosensors for characterizing nutrient metabolism in vivo

Methods for measuring gut microbiota biochemical activities in vivo are needed to characterize its functional states in health and disease. To illustrate one approach, an arabinan-containing polysaccharide was isolated from pea fiber, its structure defined, and forward genetic and proteomic analyses used to compare its effects, versus unfractionated pea fiber and sugar beet arabinan, on a human gut bacterial strain consortium in gnotobiotic mice. We produced ‘Microbiota Functional Activity Biosensors’ (MFABs) consisting of glycans covalently linked to the surface of fluorescent paramagnetic microscopic glass beads. Three MFABs, each containing a unique glycan/fluorophore combination, were simultaneously orally gavaged into gnotobiotic mice, recovered from their intestines, and analyzed to directly quantify bacterial metabolism of structurally distinct arabinans in different human diet contexts. Colocalizing pea-fiber arabinan and another polysaccharide (glucomannan) on the bead surface enhanced in vivo degradation of glucomannan. MFABs represent a potentially versatile platform for developing new prebiotics and more nutritious foods.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Vaccination with mycobacterial lipid loaded nanoparticle leads to lipid antigen persistence and memory differentiation of antigen-specific T cells

Mycobacterium tuberculosis (Mtb) infection elicits both protein and lipid antigen-specific T cell responses. However, the incorporation of lipid antigens into subunit vaccine strategies and formulations has been underexplored, and the characteristics of vaccine-induced Mtb lipid-specific memory T cells have remained elusive. Mycolic acid (MA), a major lipid component of the Mtb cell wall, is presented by human CD1b molecules to unconventional T cell subsets. These MA-specific CD1b-restricted T cells have been detected in the blood and disease sites of Mtb-infected individuals, suggesting that MA is a promising lipid antigen for incorporation into multicomponent subunit vaccines. In this study, we utilized the enhanced stability of bicontinuous nanospheres (BCN) to efficiently encapsulate MA for in vivo delivery to MA-specific T cells, both alone and in combination with an immunodominant Mtb protein antigen (Ag85B). Pulmonary administration of MA-loaded BCN (MA-BCN) elicited MA-specific T cell responses in humanized CD1 transgenic mice. Simultaneous delivery of MA and Ag85B within BCN activated both MA- and Ag85B-specific T cells. Notably, pulmonary vaccination with MA-Ag85B-BCN resulted in the persistence of MA, but not Ag85B, within alveolar macrophages in the lung. Vaccination of MA-BCN through intravenous or subcutaneous route, or with attenuated Mtb likewise reproduced MA persistence. Moreover, MA-specific T cells in MA-BCN-vaccinated mice differentiated into a T follicular helper-like phenotype. Overall, the BCN platform allows for the dual encapsulation and in vivo activation of lipid and protein antigen-specific T cells and leads to persistent lipid depots that could offer long-lasting immune responses.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

In Vivo Imaging of the Microglial Landscape After Whole Brain Radiation Therapy

Whole brain radiation therapy (WBRT) is an important treatment for patients with multiple brain metastases, but can also cause cognitive deterioration. Microglia, the resident immune cells of the brain, promote a proinflammatory environment and likely contribute to cognitive decline after WBRT. To investigate the temporal dynamics of the microglial reaction in individual mice to WBRT, we developed a novel in vivo experimental model using cranial window implants and longitudinal imaging.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Preclinical Risk Evaluation of Normal Tissue Injury With Novel Radiosensitizers

Genotoxic damage induced by radiation triggers a highly coordinated DNA damage response, and molecular inhibitors of key nodes within this complex response network can profoundly enhance the antitumor efficacy of radiation. This is especially true for drugs targeting the catalytic subunit of DNA-dependent protein kinase, which is a core component of the nonhomologous end-joining DNA repair pathway, and ataxia telangiectasia mutated, which coordinates cell cycle arrest, apoptosis, and DNA repair functionalities after radiation exposure. Unlike the more modest in vitro radiosensitizing effects seen with classic sensitizing agents such as cisplatin, 5-fluorouracil, or taxanes, DNA-dependent protein kinase or ataxia telangiectasia mutated inhibitors provide much more robust sensitizing effects in vitro, as might be anticipated from targeting these key DNA repair modulators. However, patients with homozygous inactivating mutations of ataxia telangiectasia mutated or mice with homozygous defects in DNA-dependent protein kinase (severe combined immunodeficiency) have profoundly enhanced acute normal tissue radiation reactions. Therefore, there is significant potential that the combination of small molecule inhibitors of these kinases with radiation could cause similar dose-limiting acute normal tissue toxicities. Similarly, although less understood, inhibition of these DNA repair response pathways could markedly increase the risk of late radiation toxicities. Because these potent radiosensitizers could be highly useful to improve local control of otherwise radiation-resistant tumors, understanding the potential for elevated risks of radiation injury is essential for optimizing therapeutic ratio and developing safe and informative clinical trials. In this review, we will discuss 2 straightforward models to assess the potential for enhanced mucosal toxicity in the oral cavity and small intestine established in our laboratories. We also will discuss similar strategies for evaluating potential drug–radiation interactions with regard to increased risks of debilitating late effects.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Parotid Gland Stem Cell Sparing Radiation Therapy for Patients With Head and Neck Cancer: A Double-Blind Randomized Controlled Trial

Radiation therapy for head and neck cancer frequently leads to salivary gland damage and subsequent xerostomia. The radiation response of the parotid glands of rats, mice, and patients critically depends on dose to parotid gland stem cells, mainly located in the gland's main ducts (stem cell rich [SCR] region). Therefore, this double-blind randomized controlled trial aimed to test the hypothesis that parotid gland stem cell sparing radiation therapy preserves parotid gland function better than currently used whole parotid gland sparing radiation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Therapeutic Intervention Using a Smad7-Based Tat Protein to Treat Radiation-Induced Oral Mucositis

Recent studies reported therapeutic effects of Smad7 on oral mucositis in mice without compromising radiation therapy–induced cancer cell killing in neighboring oral cancer. This study aims to assess whether a Smad7-based biologic can treat oral mucositis in a clinically relevant setting by establishing an oral mucositis model in dogs and analyzing molecular targets.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Deciphering the Dynamic Molecular Program of Radiation-Induced Endothelial Senescence

Radiation-induced cellular senescence is a double-edged sword, acting as both a tumor suppression process limiting tumor proliferation, and a crucial process contributing to normal tissue injury. Endothelial cells play a role in normal tissue injury after radiation therapy. Recently, a study observed an accumulation of senescent endothelial cells (ECs) around radiation-induced lung focal lesions following stereotactic radiation injury in mice. However, the effect of radiation on EC senescence remains unclear because it depends on dose and fractionation, and because the senescent phenotype is heterogeneous and dynamic.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Inactivated STAT5 pathway underlies a novel inhibitory role of EBF1 in chronic lymphocytic leukemia

B-cell chronic lymphocytic leukemia (CLL) is a disease caused by gradual accumulation of functionally incompetent lymphocytes. The majority of CLL cases are accompanied by chemoresistance. Early B cell factor 1 (EBF1) is a crucial contributor to B-cell lymphopoiesis. This study is to explore the effect of EBF1 on CLL cell progression and its involvement in regulating the signal transducers and activators of transcription 5 (STAT5) pathway. We conducted a correlation analysis between EBF1 and the clinical characteristics of CLL patients. Subsequently, EBF1 was overexpressed by transfection with EBF1 overexpression plasmid and the STAT5 pathway was also blocked by treatment with SH-4-54 in isolated CD20{sup +} B lymphocytes to investigate their roles in the regulation of cellular functions. STAT5, Janus kinase 2 (JAK2) expression and their phosphorylation levels were determined by quantitative PCR and Western blot analyses. The in vivo effects of EBF1 on tumor growth were evaluated using a xenotransplant model. Downregulation of EBF1 was observed in CD20{sup +} B lymphocytes of CLL patients. EBF1 overexpression disrupted the activation of STAT5 pathway, as evidenced by decreased expression and phosphorylation levels of STAT5 and JAK2. Furthermore, overexpression of EBF1 repressed viability and cell cycle entry, and increased apoptosis of CD20{sup +} B lymphocytes by inhibiting the STAT5 pathway. Finally, EBF1 exerted antitumor effects in nude mice. Overall, our study elucidates the inhibitory role of EBF1 in CLL through inactivation of the STAT5 pathway, which may provide new targets for CLL treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Ubiquitin-specific protease 14 promotes radio-resistance and suppresses autophagy in oral squamous cell carcinoma

Highlights: • USP14 promotes radioresistance of OSCC cells. • USP14 elevates radioresistance of OSCC cells by suppressing apoptosis. • USP14 modulates radioresistance in OSCC by regulating autophagy. Oral squamous cell carcinoma (OSCC) is a common malignant tumor in the world. Radiotherapy is one of the standard therapies for patients with OSCC, but its clinical efficiency is limited due to radioresistance. In this study, we identified a mechanism of such resistance regulated by Ubiquitin-specific protease 14 (USP14). USP14 expression was significantly increased in clinical OSCC tissue samples and cell lines, and OSCC patients with high USP14 expression predicted poor overall survival rate. Additionally, a negative correlation between USP14 and LC3B was observed in patients with OSCC. We then found that irradiation (IR)-reduced cell survival of OSCC cells lines was further decreased when USP14 was knocked down. However, USP14 over-expression significantly promoted the cell viability of OSCC cells after IR treatment. Colony formation analysis confirmed thatafter IR treatment,USP14 knockdown markedly decreased the proliferation of OSCC cells, but over-expressing USP14 significantly up-regulated the proliferative activity of OSCC cells. Furthermore, DNA damage caused by IR was enhanced by USP14 knockdown, while been suppressed in OSCC cells with USP14 over-expression. Additionally, IR-inducedapoptosis was further promoted by USP14 knockdown in OSCC cells, which was, however, significantly abolished by USP14 over-expression.Moreover, our in vivo studies showed that IR-reduced tumor growth and tumor weight were further enhanced by USP14 knockdown in OSCC tumor-bearing nude mice. Finally, we found that USP14 knockdown could promote IR-induced autophagy by increasing LC3BII and γH2AX expression levels in IR-treated OSCC cells. However, this event was markedly abolished by ATG5 knockdown, subsequently restoring the cell proliferation in IR-incubated OSCC cells.Finally, we found that USP14-mediated apoptosis was autophagy-dependent in IR-treated OSCC cells. Taken together, these findings suggested that suppressing USP14 could alleviateradioresistancein OSCC both in vitro and in vivo by inducing apoptosis and autophagy, and thus could be served as a promising therapeutic strategy for OSCC treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Combination therapy with lenvatinib and radiation significantly inhibits thyroid cancer growth by uptake of tyrosine kinase inhibitor

Highlights: • Lenvatinib combined with radiation significantly inhibits thyroid cancer growth. • Combined therapy induced apoptosis and G2/M phase cell cycle arrest. • Irradiation increased cellular uptake of lenvatinib into cancer cells. • Combined therapy suggests a new therapeutic strategy for advanced thyroid cancer. Although surgical treatment cures >90% of differentiated thyroid cancer (DTC) patients, the remaining patients, including advanced DTC cases, have poor clinical outcomes. These patients with inoperable disease have only two choices of radioactive iodine therapy and tyrosine kinase inhibitors such as lenvatinib, which have a high incidence of treatment-related adverse events and can only prolong progression free survival by approximately 5–15 months. In this study, we investigated the antitumor effects of combination therapy with lenvatinib and radiation (CTLR) for DTC. CTLR synergistically inhibited cell replication and colony formation in vitro and tumor growth in nude mice without apparent toxicities and suppressed the expression of proliferation marker (Ki-67). CTLR also induced apoptosis and G2/M phase cell cycle arrest. Moreover, quantitative analysis of the intracellular uptake of lenvatinib using liquid chromatography and mass spectrometry demonstrated that intracellular uptake of lenvatinib was significantly increased 48 h following irradiation. These data suggest that increased membrane permeability caused by irradiation increases the intracellular concentration of levatinib, contributing to the synergistic effect. This mechanism-based potential of combination therapy suggests a powerful new therapeutic strategy for advanced thyroid cancer with fewer side effects and might be a milestone for developing a regimen in clinical practice.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Protein 4.1R negatively regulates P815 cells proliferation by inhibiting C-Kit-mediated signal transduction

The proliferation of mast cells (MCs) plays a crucial role in either physiological or pathological progression of human physical. C-Kit-mediated signaling pathway has been confirmed to play a key role in MCs proliferation, and the regulatory mechanisms of C-Kit-mediated MCs proliferation need to be further explored. Our previous study found that protein 4.1R could negatively regulate T cell receptor (TCR) mediated signal pathways in CD4{sup +} T cells. Little is known about the function of 4.1R in C-Kit-mediated proliferation of MCs. In this study, P815-4.1R{sup -/-} cells were constructed by using CRISPR/Cas9 technique. Lack of 4.1R significantly enhanced P815 cells proliferation by accelerating the progression of cell cycle. 4.1R could also significantly alleviate the clinical symptoms of systemic mastocytosis (SM) and improve the overall survival of SM mice. Further study showed that 4.1R could interact directly with C-Kit to inhibit the activation of C-Kit-mediated Ras-Raf-MAPKs and PI3K-AKT signal pathways. Taken together, our findings demonstrate that protein 4.1R, a novel negative regulator, negatively regulates MCs proliferation by inhibiting C-Kit-mediated signal transduction, which maybe provide a potential target to the prevention and treatment of abnormal MCs proliferation-related diseases.

60 APPLIED LIFE SCIENCES↗