Engineering Papers⌕ Search

SEARCH · Engineering Papers

Results for “SPLEEN”

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.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Depletion of Fractalkine ameliorates renal injury and Treg cell apoptosis via the p38MAPK pathway in lupus-prone mice

Highlights: • FKN and p-p38 were increased in the renal of lupus mice. • Anti-FKN antibody and SB203580 ameliorated renal injury in lupus mice. • FKN KD and SB203580 reduced cell apoptosis, and suppressed p38MAPK signal in Treg cells derived from lupus mice spleen. • The p38MAPK activator U-46619 had the opposite effect in these cells. • Depletion of FKN ameliorates renal injury and Treg cell apoptosis via p38MAPK signal in lupus nephritis. Fractalkine (FKN) is a chemokine with several roles, including chemotaxis; adhesion; and immune damage, which also participates in cell inflammation and apoptosis and responds to the pathogenesis of autoimmune diseases. Given the involvement of regulatory T cells (Treg) cells in autoimmune diseases, this study investigated the regulatory mechanism of FKN in renal injury and Treg apoptosis via the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway in lupus-prone mice. Lupus was induced in BALB/c female mice by injection of pristane, followed by isolation of CD4{sup +}CD25{sup +} Treg cells from the spleen of lupus model mice. To deplete FKN, mice received injection of an anti-FKN antibody, and Treg cells were transfected with FKN small-interfering RNA. Lupus mice and Treg cells were treated with the p38MAPK inhibitor SB203580 and activator U-46619, respectively, and urine protein and serum urea nitrogen, creatinine, and autoantibodies were measured and renal histopathological changes analyzed. We determined levels of FKN, phosphorylated p38 (p-p38), and forkhead box P3 (FOXP3) in renal tissue and Treg cells, and analyzed apoptosis rates and levels of key apoptotic factors in Treg cells. The renal FKN and p-p38 levels increased, whereas renal FOXP3 level decreased in lupus-prone mice. Treatment with the anti-FKN antibody and the p38MAPK inhibitor ameliorated proteinuria and renal function, significantly reducing serum autoantibody, renal FKN, and p-p38 levels while increasing renal FOXP3 level in lupus-prone mice. Moreover, FKN knockdown and administration of the p38MAPK inhibitor reduced apoptosis and levels of pro-apoptotic factors, increased levels of anti-apoptotic factors, and suppressed activation of p38MAPK signaling in Treg cells derived from lupus model mice. Furthermore, treatment with the p38MAPK activator U-46619 had the opposite effect on these cells. These data indicated that depletion of FKN ameliorated renal injury and Treg cell apoptosis via inhibition of p38MAPK signaling in lupus nephritis, suggesting that targeting FKN represents a potential therapeutic strategy for treating Lupus nephritis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

SU-E-I-14: Comparison of Iodine-Labeled and Indium-Labeled Antibody Biodistributions

Purpose: It is often assumed that animal biodistributions of novel proteins are not dependent upon the radiolabel used in their determination. In units of percent injected dose per gram of tissue (%ID/g), organ uptake results (u) may be obtained using either iodine or metal as radioactive labels. Iodination is preferred as it is a one-step process whereas metal labeling requires two chemical procedures and therefore more protein material. It is important to test whether the radioactive tag leads to variation in the uptake value. Methods: Uptakes of 3antibodies to Carcinoembryonic Antigen (CEA) were evaluated in a nude mouse model bearing 150 to 300 mg LS174T human colon cancer xenografts. Antibodies included diabody (56 kDa), minibody (80kDa) and intact M5A (150 kDa) anti-CEA cognates. Both radioiodine and indium-111 labels were used with uptakes evaluated at 7 time(t) points out to 96 h. Ratios (R) of u(iodine-label)/u(indium-label) were determined for liver, spleen, kidneys, lung and tumor. Results: Hepatic loss was rapid for diabody and minibody; by 24 h their R values were only 2%; i.e., uptake of iodine was 2% of that of indium for these 2 antibodies. By contrast, R for the intact cognate was 50% at that time point. Splenic results were similar. Tumor uptake ratios did not depend upon the antibody type and were 50% at 24 h. Conclusions: Relatively rapid loss of iodine relative to indium in liver and spleen was observed in lower mass antibodies. Tumor ratios were larger and independent of antibody type. Aside from tumor, the R ratio of uptakes depended on the antibody type. R values decreased monotonically with time in all tissues and for all cognates. Using this ratio, one can possibly correct iodine-based u (t) results so that they resemble radiometal-derived biodistributions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

SU-E-I-28: Evaluating the Organ Dose From Computed Tomography Using Monte Carlo Calculations

Purpose: To evaluate organ doses from computed tomography (CT) using Monte Carlo (MC) calculations. Methods: A Philips Brilliance CT scanner (64 slice) was simulated using the GMctdospp (IMPS, Germany) based on the EGSnrc user code. The X-ray spectra and a bowtie filter for MC simulations were determined to coincide with measurements of half-value layer (HVL) and off-center ratio (OCR) profile in air. The MC dose was calibrated from absorbed dose measurements using a Farmer chamber and a cylindrical water phantom. The dose distribution from CT was calculated using patient CT images and organ doses were evaluated from dose volume histograms. Results: The HVLs of Al at 80, 100, and 120 kV were 6.3, 7.7, and 8.7 mm, respectively. The calculated HVLs agreed with measurements within 0.3%. The calculated and measured OCR profiles agreed within 3%. For adult head scans (CTDIvol) =51.4 mGy), mean doses for brain stem, eye, and eye lens were 23.2, 34.2, and 37.6 mGy, respectively. For pediatric head scans (CTDIvol =35.6 mGy), mean doses for brain stem, eye, and eye lens were 19.3, 24.5, and 26.8 mGy, respectively. For adult chest scans (CTDIvol=19.0 mGy), mean doses for lung, heart, and spinal cord were 21.1, 22.0, and 15.5 mGy, respectively. For adult abdominal scans (CTDIvol=14.4 mGy), the mean doses for kidney, liver, pancreas, spleen, and spinal cord were 17.4, 16.5, 16.8, 16.8, and 13.1 mGy, respectively. For pediatric abdominal scans (CTDIvol=6.76 mGy), mean doses for kidney, liver, pancreas, spleen, and spinal cord were 8.24, 8.90, 8.17, 8.31, and 6.73 mGy, respectively. In head scan, organ doses were considerably different from CTDIvol values. Conclusion: MC dose distributions calculated by using patient CT images are useful to evaluate organ doses absorbed to individual patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

SU-E-T-501: Normal Tissue Toxicities of Pulsed Low Dose Rate Radiotherapy and Conventional Radiotherapy: An in Vivo Total Body Irradiation Study

Purpose: Pulsed low dose rate radiotherapy (PLDR) is a re-irradiation technique for therapy of recurrent cancers. We have previously shown a significant difference in the weight and survival time between the mice treated with conventional radiotherapy (CRT) and PLDR using total body irradiation (TBI). The purpose of this study was to investigate the in vivo effects of PLDR on normal mouse tissues.Materials and Methods: Twenty two male BALB/c nude mice, 4 months of age, were randomly assigned into a PLDR group (n=10), a CRT group (n=10), and a non-irradiated control group (n=2). The Siemens Artiste accelerator with 6 MV photon beams was used. The mice received a total of 18Gy in 3 fractions with a 20day interval. The CRT group received the 6Gy dose continuously at a dose rate of 300 MU/min. The PLDR group was irradiated with 0.2Gyx20 pulses with a 3min interval between the pulses. The mice were weighed thrice weekly and sacrificed 2 weeks after the last treatment. Brain, heart, lung, liver, spleen, gastrointestinal, urinary and reproductive organs, and sternal bone marrow were removed, formalin-fixed, paraffin-embedded and stained with H and E. Morphological changes were observed under a microscope. Results: Histopathological examination revealed atrophy in several irradiated organs. The degree of atrophy was mild to moderate in the PLDR group, but severe in the CRT group. The most pronounced morphological abnormalities were in the immune and hematopoietic systems, namely spleen and bone marrow. Brain hemorrhage was seen in the CRT group, but not in the PLDR group. Conclusions: Our results showed that PLDR induced less toxicity in the normal mouse tissues than conventional radiotherapy for the same dose and regimen. Considering that PLDR produces equivalent tumor control as conventional radiotherapy, it would be a good modality for treatment of recurrent cancers.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

SU-C-19A-06: A Robust and Affordable Table Indexing Approach for Total Lymphoid Irradiation Treatment

Purpose: Total lymphoid irradiation (TLI) is conventionally delivered through the dosimetric matching of mantle, spleen, and pelvis fields, necessitating multiple isocenters delivered through a combination of couch shifts and sliding of patients relative to the couch rendering the technique susceptible to shifting errors. To address this challenge, a novel technique for the couch indexing of TLI treatments is developed and evaluated through a multi-patient pilot trial. Methods: An immobilization device was designed consisting of a movable indexed slide board with an Exact Lok-Bar drilled into it. A Timo headrests were used fixate the head of the patient relative to the slide board. For the Varian Exact Couch™, the immobilization board was connected to the H3 notch to avoid the metal infrastructure of the couch for the delivery of the mantle and spleen fields. For tall patients the required shift for the pelvis isocenter reaches the shifting limit and the board was slid from H3 to H4 (a fixed distance of 14 cm). A total 22 patients were stratified in two groups of 11, one consisting of the conventional setup, and one group with the proposed immobilization technique. Results: The standard deviations (SD) of the couch positions in lateral, longitudinal, and vertical directions for 10 fractions for each patient in both groups were calculated. In the non-indexed group, the positioning SD ranged from 0.9 to 4.7 cm. Using our device, the positioning SD was reduced to a range of 0.2 to 0.9 cm, with the longitudinal direction showing the largest improvement. Conclusion: Matched field TLI remains error prone to geometrical misses. The feasibility of full indexing TLI treatments was validated and shown to result in a significant reduction of positioning errors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Improved dosimetry for targeted radionuclide therapy using nonrigid registration on sequential SPECT images

Purpose: Voxel-level and patient-specific 3D dosimetry for targeted radionuclide therapy (TRT) typically involves serial nuclear medicine scans. Misalignment of the images can result in reduced dosimetric accuracy. Since the scans are typically performed over a period of several days, there will be patient movement between scans and possible nonrigid organ deformation. This work aims to implement and evaluate the use of nonrigid image registration on a series of quantitative SPECT (QSPECT) images for TRT dosimetry. Methods: A population of 4D extended cardiac torso phantoms, comprised of three In-111 Zevalin biokinetics models and three anatomical variations, was generated based on the patient data. The authors simulated QSPECT acquisitions at five time points. At each time point, individual organ and whole-body deformation between scans were modeled by translating/rotating organs and the body up to 5°/voxels, keeping ≤5% difference in organ volume. An analytical projector was used to generate realistic noisy projections for a medium energy general purpose collimator. Projections were reconstructed using OS-EM algorithm with geometric collimator detector response, attenuation, and scatter corrections. The QSPECT images were registered using organ-based nonrigid image registration method. The cumulative activity in each voxel was obtained by integrating the activity over time. Dose distribution images were obtained by convolving the cumulative activity images with a Y-90 dose kernel. Dose volume histograms (DVHs) for organs-of-interest were analyzed. Results: After nonrigid registration, the mean differences in organ doses compared to the case without misalignment were improved from (−15.50 ± 5.59)% to (−2.12 ± 1.05)% and (−7.28 ± 2.30)% to (−0.23 ± 0.71)% for the spleen and liver, respectively. For all organs, the cumulative DVHs showed improvement after nonrigid registration and the normalized absolute error of differential DVHs ranged from 6.79% to 22.70% for liver and 26.00% to 39.70% for spleen with different segmentation methods. Conclusions: These results demonstrated that nonrigid registration of sequential QSPECT images is feasible for TRT and improves the accuracy of 3D dosimetry.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Is Routine Splenectomy Justified for All Left-Sided Pancreatic Cancers? Histological Reappraisal of Splenic Hilar Lymphadenectomy

Background: Although splenectomy is recommended during resection for left-sided resectable pancreatic ductal adenocarcinoma (PDAC) to perform lymphadenectomy of station 10 (splenic hilum), no level I evidence justifies this procedure. This study aims to evaluate the rate of lymph node (LN) and contiguous involvement of the splenic hilum in resectable distal PDAC. Methods: We retrospectively reviewed all patients who underwent splenopancreatectomy for PDAC in the past 10 years. Station 10 LN were routinely isolated, and all corresponding microscopic slides were reinterpreted by a pathologist. The computed tomography (CT) results of patients with tumoral involvement of the spleen or splenic hilum by contiguity (TISOSH) and ≤ 10 mm between the tumor and spleen on pathology were blindly reviewed by two radiologists to evaluate CT for diagnosis of TISOSH. Results: We included 110 consecutive patients, including 104 with analyzable station 10 LN. The tumor was N+ in 58 (53%) patients. The median number of LN identified at station 10 was 2.0 ± 3.0. No station 10 LNs were detected in 42 (40%) patients. No patients had tumor-positive LN at station 10. TISOSH was found in nine (8%) patients, and was significantly associated with tail location (p = 0.001), tumor size (p = 0.005), and multivisceral involvement (p = 0.015). For diagnosis of TISOSH, the sensitivity and specificity of CT were respectively 89% and 95% for radiologist 1 and 89% and 100% for radiologist 2. Conclusions: Splenic preservation during resection of distal PDAC may be an option in selected patients with body tumors and no suspected splenic or splenic hilum involvement on preoperative CT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

In Patients with Localized and Resectable Gastric Cancer, What is the Optimal Extent of Lymph Node Dissection—D1 Versus D2 Versus D3?

Background: Despite advances in the treatment of patients with gastric cancer, the debate over the optimal extent of lymphadenectomy continues. Method: A review of the classification, rationale for, and boundaries of lymphadenectomy is presented. A review of the available literature comparing D1 versus D2 versus D3 lymphadenectomy was performed and included randomized controlled trials, and prospective and retrospective comparative and non-comparative studies. Results: Earlier studies demonstrated increased morbidity with D2 compared with D1 lymphadenectomy, with no significant survival benefit. More recent studies have demonstrated survival benefit of a pancreas and spleen-sparing D2 lymphadenectomy in patients with advanced, node-positive tumors. Para-aortic/D3 dissections contribute to increased morbidity, with no survival benefit. Conclusions: In patients with resectable gastric adenocarcinoma, a D2 lymph node dissection preserving the pancreas and spleen should be considered standard for optimal staging and treatment, provided it is performed by surgeons with sufficient expertise. Extended lymph node dissections beyond D2 should not be routinely performed as it has been shown to have increased morbidity, with no improvement in outcomes. While systemic chemotherapy should be considered standard in patients undergoing D2 lymphadenectomy, the role of adjuvant radiation continues to evolve.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress effector T cell responses and can reduce the efficacy of cancer immunotherapies. We previously showed that ultra-small polymer nanoparticles efficiently drain to the lymphatics after intradermal injection and target antigen-presenting cells, including Ly6c hi Ly6g ₋ monocytic MDSCs (Mo-MDSCs), in skin-draining lymph nodes (LNs) and spleen. Here, we developed ultra-small polymer micelles loaded with 6-thioguanine (MC-TG), a cytotoxic drug used in the treatment of myelogenous leukemia, with the aim of killing Mo-MDSCs in tumor-bearing mice and thus enhancing T cell-mediated anti-tumor responses. We found that 2 days post-injection in tumor-bearing mice (B16-F10 melanoma or E.G7-OVA thymoma), MC-TG depleted Mo-MDSCs in the spleen, Ly6c lo Ly6g + granulocytic MDSCs (G-MDSCs) in the draining LNs, and Gr1 int Mo-MDSCs in the tumor. In both tumor models, MC-TG decreased the numbers of circulating Mo- and G-MDSCs, as well as of Ly6c hi macrophages, for up to 7 days following a single administration. MDSC depletion was dose dependent and more effective with MC-TG than with equal doses of free TG. Finally, we tested whether this MDSC-depleting strategy might enhance cancer immunotherapies in the B16-F10 melanoma model. We found that MC-TG significantly improved the efficacy of adoptively transferred, OVA-specific CD8 + T cells in melanoma cells expressing OVA. Ultimately, these findings highlight the capacity of MC-TG in depleting MDSCs in the tumor microenvironment and show promise in promoting anti-tumor immunity when used in combination with T cell immunotherapies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

4-1BB Aptamer-Based Immunomodulation Enhances the Therapeutic Index of Radiation Therapy in Murine Tumor Models

Purpose: To report a novel strategy using oligonucleotide aptamers to 4-1BB as an alternate method for costimulation, and show that combinatorial therapy with radiation improves the therapeutic ratio over equivalent monoclonal antibodies. Methods and Materials: Subcutaneous 4T1 (mouse mammary carcinoma) tumors were established (approximately 100 mm{sup 3}), and a radiation therapy (RT) dose/fractionation schedule that optimally synergizes with 4-1BB monoclonal antibody (mAb) was identified. Comparable tumor control and animal survival was observed when either 4-1BB antibody or aptamer were combined with RT using models of breast cancer and melanoma (4T1 and B16-F10). Off-target CD8{sup +} T-cell toxicity was evaluated by quantification of CD8{sup +} T cells in livers and spleens of treated animals. Results: When combined with 4-1BB mAb, significant differences in tumor control were observed by varying RT dose and fractionation schedules. Optimal synergy between RT and 4-1BB mAb was observed at 5 Gy × 6. Testing 4-1BB mAb and aptamer independently using the optimal RT (5 Gy × 6 for 4T1/Balb/c and 12 Gy × 1 for B16/C57BL6J mouse models) revealed equivalent tumor control using 4-1BB aptamer and 4-1BB mAb. 4-1BB mAb, but not 4-1BB aptamer-treated animals, exhibited increased lymphocytic liver infiltrates and increased splenic and liver CD8{sup +} T cells. Conclusions: Radiation therapy synergizes with 4-1BB mAb, and this effect is dependent on RT dose and fractionation. Tumor control by 4-1BB aptamer is equivalent to 4-1BB mAb when combined with optimal RT dose, without eliciting off-target liver and spleen CD8{sup +} expansion. 4-1BB aptamer-based costimulation affords a comparable and less toxic strategy to augment RT-mediated tumor control.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Benchmarking Bicontinuous Nanospheres against Polymersomes for in Vivo Biodistribution and Dual Intracellular Delivery of Lipophilic and Water-Soluble Payloads

Bicontinuous nanospheres (BCNs) are polymeric analogs to lipid cubosomes, possessing cubic liquid crystalline phases with high internal surface area, aqueous channels for loading hydrophilic molecules, and high hydrophobic volume for lipophilic payloads. Primarily due to difficulties in scalable and consistent fabrication, neither controlled delivery of payloads via BCNs nor their organ or cellular biodistributions following in vivo administration have been demonstrated or characterized. We have recently validated flash nanoprecipitation as a rapid method of assembling uniform monodisperse 200–300 nm diameter BCNs from poly(ethylene glycol)-$b$-poly(propylene sulfide) (PEG-$b$-PPS) co-polymers. In this work, we compare these BCNs both in vitro and in vivo to 100 nm PEG-$b$-PPS polymersomes (PSs), which have been well characterized as nanocarriers for controlled delivery applications. Using a small molecule fluorophore and a fluorescently tagged protein as respective lipophilic and water-soluble model cargos, we demonstrate that BCNs can achieve significantly higher encapsulation efficiencies for both payloads on a per unit mass basis. At time points of 4 and 24 h after intravenous administration to mice, we found significant differences in organ-level uptake between BCNs and PSs, with BCNs showing reduced accumulation in the liver and increased uptake in the spleen. Despite these organ-level differences, BCNs and PSs displayed strikingly similar uptake profiles by immune cell populations in vitro and in the liver, spleen, and blood, as assayed by flow cytometry. In conclusion, we have found PEG-$b$-PPS BCNs to be well suited for dual loading and delivery of molecular payloads, with a favorable organ biodistribution and high cell uptake by therapeutically relevant immune cell populations.

36 MATERIALS SCIENCE↗
DOE OSTI2018

Establishing the effects of mesoporous silica nanoparticle properties on in vivo disposition using imaging-based pharmacokinetics

Abstract The progress of nanoparticle (NP)-based drug delivery has been hindered by an inability to establish structure-activity relationships in vivo. Here, using stable, monosized, radiolabeled, mesoporous silica nanoparticles (MSNs), we apply an integrated SPECT/CT imaging and mathematical modeling approach to understand the combined effects of MSN size, surface chemistry and routes of administration on biodistribution and clearance kinetics in healthy rats. We show that increased particle size from ~32- to ~142-nm results in a monotonic decrease in systemic bioavailability, irrespective of route of administration, with corresponding accumulation in liver and spleen. Cationic MSNs with surface exposed amines (PEI) have reduced circulation, compared to MSNs of identical size and charge but with shielded amines (QA), due to rapid sequestration into liver and spleen. However, QA show greater total excretion than PEI and their size-matched neutral counterparts (TMS). Overall, we provide important predictive functional correlations to support the rational design of nanomedicines.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Robust collection and processing for label-free single voxel proteomics

With advanced mass spectrometry (MS)-based proteomics, genome-scale proteome coverage can be achieved from bulk tissues. However, such bulk measurement lacks spatial resolution and obscures tissue heterogeneity, precluding proteome mapping of tissue microenvironment. Here we report an integrated $\underline{w}et$ $\underline{c}ollection$ of single microscale tissue voxels and $\underline{S}urfactant$$-assisted$ $\underline{O}ne$-$\underline{P}ot$ voxel processing method termed wcSOP for robust label-free single voxel proteomics. wcSOP capitalizes on buffer droplet-assisted wet collection of a single voxel dissected by LCM into the PCR tube cap and MS-compatible surfactant-assisted one-pot voxel processing in the collection cap. This convenient method allows reproducible label-free quantification of ~900 and ~4,600 proteins for single voxels at 20 µm × 20 µm × 10 µm (close to single cells) and 200 µm × 200 µm × 10 µm (~100 cells) from fresh frozen human spleen tissue, respectively. 100s-1000s of protein signatures were spatially resolved between spleen red and white pulp regions depending on the voxel size. Region-specific signaling pathways were enriched from single voxel proteomics data. To evaluate its broad applicability, we applied wcSOP-MS to two commonly accessible, OCT-embedded and FFPE, human archived tissues. It enabled to identify spatially resolved proteome changes and enriched pathways between diseased (breast cancer tumor or AD amyloid plaque) and adjacent normal regions. Antibody-based CODEX and IHC imaging validated label-free MS quantitation for single voxel analysis. The wcSOP-MS method paves the way for routine robust single voxel proteomics and spatial proteomics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

TH-CD-207B-12: Quantification of Clinical Feedback On Image Quality Differences Between Two CT Scanner Models

Purpose: This work sought to quantify a radiology team’s assessment of image quality differences between two CT scanner models currently in clinical use, with emphasis on noise and low-contrast detectability (LCD). Methods: A water phantom and a Kagaku anthropomorphic body phantom were scanned on GE Discovery CT750 HD and LightSpeed VCT scanners (4 each) with identical scan parameters and reconstructed to 2.5mm/5.0mm thicknesses. Images of water phantom were analyzed at the scanner console with a built-in LCD tool that uses statistical methods to compute requisite CT-number contrast for 95% confidence in detection of a user-defined object size. LCD value was computed for 5mm, 3mm, and 1mm objects. Analysis of standard deviation and LCD values were performed on Kagaku phantom images within liver, stomach, and spleen. LCD value was computed for 4mm, 3mm, and 1mm objects using a benchmarked MATLAB implementation of the GE scanner-console tool. Results: Water LCD values were larger (poorer performance) for all HD scanners compared to VCT scanners. Mean scanner model difference in requisite CT-number contrast for 5mm, 3mm, and 1mm objects for 5.0mm/2.5mm images was 3.0%/3.4% (p=0.02/p=0.10), 5.3%/5.7% (0.00002/0.02), and 8.5%/8.2% (0.0004/0.002), respectively. Mean standard deviations within Kagaku phantom ROIs were greater in HD compared to VCT images, with mean differences for the liver, stomach, and spleen for 5.0mm/2.5mm of 16%/12% (p=0.04/0.10), 8%/12% (0.15/0.11), and 16%/15% (0.05/0.11), respectively. Mean LCD value difference between HD and VCT scanners over all ROIs for 4mm, 3m, and 1mm objects and 5.0mm/2.5mm was 34%/9%, 16%/8%, and 18%/10%, respectively. HD scanners outperformed VCT scanners only for the 4mm stomach object. Conclusion: Using both water and anthropomorphic phantoms, it was shown that HD scanners are outperformed by VCT scanners with respect to noise and LCD in a consistent and in most cases statistically significant manner. The relationship between statistical and clinical significance demands further work.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Evaluating the potential of gold, silver, and silica nanoparticles to saturate mononuclear phagocytic system tissues under repeat dosing conditions

Background: As nanoparticles (NPs) become more prevalent in the pharmaceutical industry, questions have arisen from both industry and regulatory stakeholders about the long term effects of these materials. This study was designed to evaluate whether gold (10 nm), silver (50 nm), or silica (10 nm) nanoparticles administered intravenously to mice for up to 8 weeks at doses known to be sub-toxic (non-toxic at single acute or repeat dosing levels) and clinically relevant could produce significant bioaccumulation in liver and spleen macrophages. Results: Repeated dosing with gold, silver, and silica nanoparticles did not saturate bioaccumulation in liver or spleen macrophages. While no toxicity was observed with gold and silver nanoparticles throughout the 8 week experiment, some effects including histopathological and serum chemistry changes were observed with silica nanoparticles starting at week 3. No major changes in the splenocyte population were observed during the study for any of the nanoparticles tested. Conclusions: The clinical impact of these changes is unclear but suggests that the mononuclear phagocytic system is able to handle repeated doses of nanoparticles.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Multiplexed Digital mRNA Profiling of the Inflammatory Response in the West Nile Swiss Webster Mouse Model

Background and purpose: The ability to track changes in gene expression following viral infection is paramount to understanding viral pathogenesis. This study was undertaken to evaluate the nCounter, a high throughput digital gene expression system, as a means to better understand West Nile virus (WNV) dissemination and the inflammatory response against WNV in the outbred Swiss Webster (SW) mouse model over the course of infection. Methodology: The nCounter Mouse Inflammation gene expression kit containing 179 inflammation related genes was used to analyze gene expression changes in multiple tissues over a nine day course of infection in SW mice following intraperitoneal injection with WNV. Protein expression levels for a subset of these cytokine/chemokine genes were determined using a multiplex protein detection system (BioPlex) and comparisons of protein/RNA expression levels made. Results: Expression analysis of spleen, lung, liver, kidney and brain of SW mice infected with WNV revealed that Cxcl10 and Il12b are differentially expressed in all tissues tested except kidney. Data stratification of positively confirmed infected (WNV (+)) versus non-infected (WNV (2) tissues allowed differentiation of the systemic inflammatory gene response from tissue specific responses arising from WNV infection. Significant (p,0.05) decrease in C3ar1 was found in WNV (2) spleen. Il23a was significantly upregulated, while Il10rb was down-regulated in WNV (2) lung. Il3 and Mbl2 were down-regulated in WNV (2) liver. In WNV (+) livers, Stat1, Tlr2, chemokines Cxcl1, Cxcl3, Cxcl9, Cxcl10, cytokines Il6, Il18, cytokine-related gene Il1r and cytokine agonist Ilrn were significantly upregulated. In WNV (2) brain tissues, Csf2 and Cxcl10 were significantly upregulated. Similar gene and protein expression kinetics were found for Ccl2, Ccl3, Ccl4 and Ccl5 and correlated with the presence of infectious virus. In summary, the utility of the nCounter platform for rapid identification of gene expression changes in SW mice associated with WNV infection was demonstrated.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Lactiplantibacillus plantarum 0111 Protects Against Influenza Virus by Modulating Intestinal Microbial-Mediated Immune Responses

There are some limitations of traditional influenza vaccines concerning novel mutant strains. Therefore, it is particularly important to develop preventive means for antigen-unrelated types of influenza viruses. Recent studies have shown that probiotics can modulate the immune system and reduce the severity of viral infections. In this study, we investigated the potential of Lactiplantibacillus plantarum 0111 against influenza virus H9N2. Challenge experiments showed that L. plantarum 0111 pretreatments could effectively improve mice’s survival rate and weight loss and reduce the inflammatory cytokines IL-6 and TNF-α in the lungs and bronchoalveolar lavage fluid (BALF) along with the degree of lung and intestinal injury. FMT experiment demonstrates that the protective effect produced by L. plantarum 0111 is associated with gut microorganisms. In addition, 16S high-throughput sequencing of the mouse intestinal microbiota showed that L. plantarum 0111 remodeled the intestinal microbiota after H9N2 infection and maintained the gut microbiota balance. In a mouse model, the oral administration of L. plantarum 0111 increased IFN-β expression in the serum and BALF. At the same time, the transcript levels of IFN-β and related ISGs in the intestine and lungs of mice were also increased. In addition, the activation and polarization of T cells in mesenteric lymph nodes (MLNs) and the spleen were detected by flow cytometry, and the results showed that L. plantarum 0111 modulated cytokines in T cells and increased IgA expression in B cells in the MLNs and spleen. Thus, L. plantarum 0111 may improve gut microbiota-mediated immune responses and thus, resist infection by the influenza virus, and it could be used as an effective preventive measure against the influenza virus.

Xing, Jun-Hong↗