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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 847 records · Page 47
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Splenic Arterial Embolization in the Treatment of Severe Portal Hypertension Due to Pancreatic Diseases: The Primary Experience in 14 Patients

ObjectiveThis retrospective study reports our experience using splenic arterial particle embolization and coil embolization for the treatment of sinistral portal hypertension (SPH) in patients with and without gastric bleeding.MethodsFrom August 2009 to May 2012, 14 patients with SPH due to pancreatic disease were diagnosed and treated with splenic arterial embolization. Two different embolization strategies were applied; either combined distal splenic bed particle embolization and proximal splenic artery coil embolization in the same procedure for acute hemorrhage (1-step) or interval staged distal embolization and proximal embolization in the stable patient (2-step). The patients were clinically followed.ResultsIn 14 patients, splenic arterial embolization was successful. The one-step method was performed in three patients suffering from massive gastric bleeding, and the bleeding was relieved after embolization. The two-step method was used in 11 patients, who had chronic gastric variceal bleeding or gastric varices only. The gastric varices disappeared in the enhanced CT scan and the patients had no gastric bleeding during follow-up.ConclusionsSplenic arterial embolization, particularly the two-step method, proved feasible and effective for the treatment of SPH patients with gastric varices or gastric variceal bleeding.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Diagnosis and Prognosis of Coronary Artery Disease with SPECT and PET

Purpose of Review: Radionuclide myocardial perfusion imaging (MPI) continues to be the most reliable modality for diagnosis of hemodynamically significant coronary artery disease (CAD). The application of radionuclide MPI using single photon emission computed tomography (SEPCT) and positron emission tomography (PET) for CAD is reviewed, with emphasis on diagnosis and risk stratification. Recent Findings: Contemporary studies have reported the diagnostic and prognostic value of novel imaging protocols, employing stress-first or stress-only approach. In addition, the superior diagnostic value of PET has been established with a role of assessment of myocardial blood flow to improve risk stratification. The utility of MPI in special populations, such as the elderly, women, and diabetic patients has also been recently evaluated. Furthermore, multicenter studies have reported a similar diagnostic and prognostic value of radionuclide MPI compared with other functional and anatomical techniques for CAD. Summary: Radionuclide MPI with SPECT and PET are efficacious for diagnosis and prognosis of CAD. Its universal application in varied patient populations highlights its excellent clinical effectiveness.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Functional and Anatomical Imaging in Patients with Ischemic Symptoms and Known Coronary Artery Disease

Purpose of Review: This review is aimed at summarizing recent advances in functional, anatomical, and hybrid imaging techniques used in the assessment of ischemic complaints in patients with known coronary artery disease (CAD). Recent Findings: Cardiovascular imaging has seen significant growth over the last decade in the fields of coronary computed tomography angiography (CCTA), FFR derived from CCTA, cardiac magnetic resonance, radionuclide myocardial perfusion imaging, and hybrid imaging for the purposes of evaluating symptoms concerning for ischemia. This growth stems from refinement of imaging techniques and hardware and software advances that have made current techniques more accurate with less acquisition time. However, every anatomic and functional imaging modality has important technical and patient-specific limitations. This review assesses these issues, guides a patient-centered imaging approach, and identifies important research questions to resolve. Summary: Recent advances in non-invasive cardiovascular imaging can provide important information in patients with known CAD beyond traditional imaging techniques; the use of these novel tools refines the clinical management of complex patients with ischemic symptoms and known CAD.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Cancer Treatment-Associated Pericardial Disease: Epidemiology, Clinical Presentation, Diagnosis, and Management

Purpose of Review: Cancer therapeutics have seen tremendous growth in the last decade and have been effective in the treatment of several cancer types. However, with advanced therapies like kinase inhibitors and immunotherapies, there have been unintended consequences of cardiotoxicities. While traditional chemotherapy and radiation-induced cardiotoxicity have been well studied, further research is needed to understand the adverse effects of newer regimens. Recent Findings: Both immune-mediated and non-immune-medicated cytotoxicity have been noted with targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. In this manuscript, we describe the pericardial syndromes associated with cancer therapies and propose management strategies. Pericardial effusion and pericarditis are common presentations in cancer patients and often difficult to diagnose. Concomitant myocarditis may also present with pericardial toxicity, especially with immunotherapies. In addition to proper history and physical, additional testing such as cardiovascular imaging and tissue histology need to be obtained as appropriate. Holding the offending oncology drug, and institution of anti-inflammatory medications, and immunosuppressants such as steroids are indicated. Summary: A high index of suspicion, use of standardized definitions, and comprehensive evaluation are needed for early identification, appropriate treatment, and better outcomes for patients with cancer treatment-associated pericardial disease. Further research is needed to understand the pathophysiology and to evaluate how the management of pericardial conditions in these patients differ from traditional management and also evaluate new therapies.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Tumor expression and usefulness as a biomarker of programmed death ligand 1 in advanced non-small cell lung cancer patients with preexisting interstitial lung disease

In non-small cell lung cancer (NSCLC) patients, the expression of tumor programmed death ligand 1 (PD-L1) is an important parameter for deciding the timing of the use of anti-programmed cell death 1 (PD-1) antibody. There has been increasing concern over the benefit of anti-PD-1 antibody in high-risk patients, such as those with preexisting interstitial lung disease (ILD). However, the status and value of PD-L1 as a predictive biomarker and the efficacy of anti-PD-1 antibody in NSCLC patients with preexisting ILD remains uncertain. We retrospectively reviewed the medical records of advanced/recurrent NSCLC patients who had undergone analysis of the tumor PD-L1 expression. We identified 358 patients with advanced/recurrent NSCLC who had undergone analysis of tumor PD-LI expression. Of these, 210 received anti-PD-1 antibody. Tumor-cell PD-L1 expression was similar between the groups with and without preexisting ILD (median, 35%; interquartile range, 0–70%; vs. median, 10%; interquartile range, 1–68%; p = 0.66). Of the 210 patients who received anti-PD-1 antibody, 14 patients had preexisting ILD. The progression-free survival (PFS) showed no significant difference between the patients receiving anti-PD-1 antibody with and without preexisting ILD (median PFS, 4.3 vs. 5.3 months; HR, 0.97; p = 0.84). Within the patients with preexisting ILD, the PFS was tended to be longer in the patients with tumor PD-L1 expression ≥ 50% than in those with tumor PD-L1 expression < 50% (median PFS, 12.5 vs. 2.5 months; HR, 0.47; p = 0.14). The value of PD-L1 expression as a biomarker may be comparable between patients with and without preexisting ILD.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

The prognostic value of heart rate response during vasodilator stress myocardial perfusion imaging in patients with end-stage renal disease undergoing renal transplantation

Background: In asymptomatic end-stage renal disease (ESRD) patients undergoing vasodilator stress myocardial perfusion imaging (MPI) prior to renal transplantation (RT), the impact of pre-transplant heart rate response (HRR) to vasodilator stress on post-RT outcomes is unknown. Methods: We analyzed a retrospective cohort of asymptomatic patients with ESRD who underwent a vasodilator stress SPECT-MPI and subsequently received RT. Blunted HRR was defined as HRR <28% for regadenoson stress and <20% for adenosine stress. The primary endpoint was major adverse cardiac events (MACE), defined as cardiac death or myocardial infarction. Clinical risk was assessed using the sum of risk factors set forth by the AHA/ACCF consensus statement on the assessment of RT candidates. Results: Among 352 subjects, 140 had an abnormal pre-transplant HRR. During a mean follow-up of 3.2 ± 2.0 years, 85 (24%) MACEs were observed. Blunted HRR was associated with increased MACE risk (hazard ratio 1.72; 95% confidence interval 1.12-2.63, P = 0.013), and remained significant after adjustment for gender, sum of AHA/ACCF risk factors, summed stress score, baseline heart rate, and β-blocker use. HRR was predictive of MACE in patients with normal MPI and irrespective of clinical risk. Blunted HRR was associated with a significant increase in post-operative (30-day) MACE risk (17.9% vs 8.5%; P = 0.009). Conclusion: In asymptomatic ESRD patients being evaluated for RT, a blunted pre-transplant HRR was predictive of post-RT MACE. HRR may be a valuable tool in the risk assessment of RT candidates.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Complete revascularization determined by myocardial perfusion imaging could improve the outcomes of patients with stable coronary artery disease, compared with incomplete revascularization and no revascularization

Objectives: To compare the outcomes among patients treated by complete coronary revascularization (CCR) or incomplete coronary revascularization (ICR) and no coronary revascularization (NCR) by myocardial perfusion imaging (MPI), as well as to evaluate the impact of severity of ischemia on patients with coronary artery disease (CAD) by different therapy strategies. Background: Using myocardial ischemia severity determined by MPI guiding treatment strategies for CAD patients still lacks strong clinical evidences. Methods: Consecutive patients (N = 286) underwent clinical stress-rest SPECT MPI and were retrospectively followed-up. For assessment of outcome of treatment, all patients were classified into three groups (CCR, ICR, and NCR), and further divided into two subgroups as mild ischemia (< 10% ischemic myocardium) and moderate-severe ischemia (≥ 10% ischemic myocardium). All-cause death was defined as the primary endpoint, and the composite of deaths, nonfatal myocardial infarction, and repeat revascularization (MACE) as the secondary endpoint. Results: Two-hundred eighty-six patients were followed-up for 46 ± 21 months. Thirty deaths and 65 MACEs were recorded. Patients treated by revascularization had significantly lower MACE (P < .001) but not mortality (P = .158) than patients treated by NCR. Outcomes of CCR related to mortality rate were greater than ICR and NCR (death: P = .019, MACE: P < .001). In patients with moderate-severe ischemia, CCR showed improved outcomes than ICR and NCR (death: P = .034; and MACE: P < .001). In patients with mild ischemia, the outcomes of CCR, ICR, and NCR had no significant difference (P > .05). Multivariate regression Cox analysis revealed that summed difference score [death: HR 1.09 (1.03, 1.15), P = .004] was an independent risk factor and CCR was an independent negative predictor [death: HR 0.31 (0.12, 0.81), P = .017; MACE: HR 0.30 (0.16, 0.57), P < .001]. Conclusions: Outcomes of patients treated by CCR were most likely more promising in comparison with treatment of ICR and NCR, especially when patients had over 10% ischemic myocardium.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Coronary vascular age: An alternate means for predicting stress-induced myocardial ischemia in patients with suspected coronary artery disease

Background: Coronary artery calcium (CAC) can be used to estimate vascular age in adults, providing a convenient transformation of CAC from Agatston units into a year’s scale. We investigated the role of coronary vascular age in predicting stress-induced myocardial ischemia in subjects with suspected coronary artery disease (CAD). Methods: A total of 717 subjects referred to CAC scoring and {sup 82}Rb PET/CT stress-rest myocardial perfusion imaging for suspected CAD were studied. CAC score was measured according to the Agatston method and coronary vascular age by equating estimated CAD risk for chronological age and CAC using the formula 39.1 + 7.25 × ln(CAC + 1). Results: Stress-induced ischemia was present in 105 (15%) patients. Mean chronological age, CAC score, and coronary vascular age were higher (all P < .001) in patients with ischemia compared to those without. At incremental analysis, the global Chi square increased from 41.26 to 68.77 (P < .001) when chronological age was added to clinical variables. Including vascular age in the model, the global Chi square further increased from 68.77 to 106.38 (P < .001). Adding chronological age to clinical data, continuous net reclassification improvement (cNRI) was 0.57, while adding vascular age to clinical data and chronological age cNRI was 0.62. At decision curve analysis, the model including vascular age was associated with the highest net benefit compared to the model including only clinical data, to the model including chronological age and clinical data, and to a strategy considering that all patients had ischemia. The model including vascular age also showed the largest reduction in false-positive rate without missing any ischemic patients. Conclusions: In subjects with suspected CAD, coronary vascular age is strongly associated with stress-induced ischemia. The communication of a given vascular age would have a superior emotive impact improving observance of therapies and healthier lifestyles.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Dual-Energy CT Pulmonary Angiography: Quantification of Disease Burden and Impact on Management

Purpose of Review: Computed tomography pulmonary angiography (CTPA) has become the imaging modality of choice for patients with suspected pulmonary embolism (PE). Post-processing techniques currently available for dual-energy CT pulmonary angiography (DE-CTPA) enhance image quality and provide additional value in the diagnosis of PE. The objective of this article is to summarize these recent developments and discuss the appropriate use of DE-CTPA post-processing applications. Recent Findings: DE-CTPA post-processing applications enable reconstruction of virtual monoenergetic images (VMI) and color-coded iodine-perfusion maps to increase contrast conditions and visualize lung perfusion defects in case of embolic occlusion of pulmonary arteries. Both techniques revealed a superior diagnostic performance for the detection of pulmonary emboli and assessment of the pulmonary perfusion compared to the standard image reconstructions. Summary: DE-CTPA is a well-established method for excluding or diagnosing PE. Continued developments in DE-CTPA post-processing techniques improve patient management and allow for a quantification of disease burden.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

Emerging Tools to Support DILI Assessment in Clinical Trials with Abnormal Baseline Serum Liver Tests or Pre-existing Liver Diseases

Abstract Based on the late Dr. Hyman Zimmerman’s observation that hepatocellular drug-induced liver injury (DILI) leading to jaundice carries a ≥ 10% fatality risk (coined as Hy’s law by others), evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) continues to play a central role in the assessment of a study drug’s liability for acute hepatocellular DILI. The eDISH identifies drugs in clinical trials with DILI fatality (death or transplant) risk that may be unacceptable in a post-market setting. As a two-dimensional graph that plots peak total bilirubin (TB) versus peak serum aminotransferase levels for each patient during study drug or comparator treatment, eDISH identifies potential cases of acute, modest, and serious hepatocellular DILI for in-depth analysis of liver tests (LT) and clinical course so that the likelihood of causal association with the study drug can be determined. Unfortunately, the generalizable utility of this tool only pertains to trials enrolling patients with normal or near normal (NNN) baseline (BL) serum LTs. The eDISH does not necessarily apply to trials of patients with abnormal baseline (ABN-BL) LTs that often coincide with underlying liver disorders. Because drug development programs being reviewed by the FDA increasingly target liver disorders, we are often challenged to evaluate DILI risk in trials of patients with ABN-BL LTs. Also, the high background prevalence of metabolic dysfunction associated steatotic liver disease (MASLD) means patients with LTs above NNN may need to be enrolled in trials treating non-liver disorders to reflect the target population. Such study populations create challenges for industry and regulators because eDISH may not reliably categorize or identify potential cases of DILI for further analysis, as it so efficiently does in NNN-BL trials. We describe the main functionalities of eDISH in NNN-BL trials to understand what should be emulated by new tools or eDISH modifications. We then discuss non-eDISH–based plots that may be useful in ABN-BL trials.

Amirzadegan, Jasmine↗
DOE OSTI2022

Tissue replication and mucosal swab detection of Sosuga virus in Syrian hamsters in the absence of overt tissue pathology and clinical disease

Human infection with Sosuga virus (SOSV), a recently discovered pathogenic paramyxovirus, has been reported in one individual to date. No animal models of disease are currently available for SOSV. Here, we describe initial characterization of experimental infection in Syrian hamsters, including kinetics of virus dissemination and replication, and the corresponding clinical parameters, immunological responses, and histopathology. Here, we demonstrate susceptibility of hamsters to infection in the absence of clinical signs or significant histopathologic findings in tissues.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Osteopontin attenuates acute gastrointestinal graft-versus-host disease by preventing apoptosis of intestinal epithelial cells

Background and aims: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation, which often targets gastrointestinal (GI) tract. Osteopontin (OPN) plays an important physiological role in the efficient development of Th1 immune responses and cell survival by inhibiting apoptosis. The role of OPN in acute GI-GVHD is poorly understood. In the present study, we investigated the role of OPN in donor T cells in the pathogenicity of acute GI-GVHD. Methods: OPN knockout (KO) mice and C57BL/6 (B6) mice were used as donors, and (C57BL/6 × DBA/2) F1 (BDF1) mice were used as allograft recipients. Mice with acute GI-GVHD were divided into three groups: the control group (BDF1→BDF1), B6 group (B6→BDF1), and OPN-KO group (OPN-KO→BDF1). Bone marrow cells and spleen cells from donors were transplanted to lethally irradiated recipients. Clinical GVHD scores were assessed daily. Recipients were euthanized on day 7 after transplantation, and colons and small intestines were collected for various analyses. Results: The clinical GVHD score in the OPN-KO group was significantly increased compared with the B6 and control groups. We observed a difference in the severity of colonic GVHD between the OPN-KO group and B6 group, but not small intestinal-GVHD between these groups. Interferon-γ, Tumor necrosis factor-α, Interleukin-17A, and Interleukin-18 gene expression in the OPN-KO group was differed between the colon and small intestine. Flow cytometric analysis revealed that the fluorescence intensity of splenic and colonic CD8 T cells expressing Fas Ligand was increased in the OPN-KO group compared with the B6 group. Conclusion: We demonstrated that the importance of OPN in T cells in the onset of acute GI-GVHD involves regulating apoptosis of the intestinal cell via the Fas-Fas Ligand pathway. - Highlights: • A lack of osteopontin in donor cells exacerbated clinical gastrointestinal GVHD. • Donor cells lacking osteopontin affected intestinal inflammation of GVHD. • Donor cells lacking osteopontin increased apoptotic epithelial cells in GVHD. • Osteopontin plays an anti-inflammatory role in acute gastrointestinal GVHD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

sRAGE prolonged stem cell survival and suppressed RAGE-related inflammatory cell and T lymphocyte accumulations in an Alzheimer's disease model

Highlights: • The interactions between RAGE and Aβ cause inflammatory responses and oxidative stress, and reduce cerebral blood flow. • RAGE and its ligand interactions induce a cascade related to neuronal apoptosis and inflammation. • The soluble form of RAGE (sRAGE) might suppress downregulation of the RAGE-mediated inflammatory/cell death pathway. • sRAGE-MSCs enhanced survival more effectively than MSCs in an Aβ{sub 1-42} induced rat model of AD. The main causes of Alzheimer's disease (AD) have not determined and effective treatment has not been developed yet, even though extensive researches and several clinical trials have been conducted.. Fortunately, stem cell transplantation is emerging as a potential therapeutic candidate for AD, but the success of stem cell based therapy depends on the survival of transplanted cells. Here, we generated sRAGE secreting mesenchymal stem cells (sRAGE-MSCs) and then injected these MSCs or control MSCs with amyloid beta 1–42 (Aβ{sub 1-42}) into the entorhinal cortices of male Sprague Dawley rats. The survival of transplanted cell, the number of T lymphocytes and microglia, expression of RAGE and its ligands and neuronal cell death were determined, 4 weeks after sRAGE-MSC transplantation. Transplanted sRAGE-MSCs survived longer than control MSCs and sRAGE-MSCs showed reduced level of CD4 and CD3d positive T lymphocyte. Furthermore, the number of M1 microglia in MSCs was more than that of sRAGE-MSCs as well. On the other hand, the number of M2 microglia in sRAGE-MSCs was increased compared with that of MSCs. In addition, sRAGE-MSCs decreased RAGE and RAGE ligand expressions and their interactions more effectively than those of MSCs. Finally, sRAGE-MSC transplantation protected from apoptosis and prevented decreasing numbers of neuron in Aβ{sub 1-42} treated rat brains. These observations suggest continuous sRAGE secretion from sRAGE-MSCs might appreciably improve the effectiveness of cell therapy in Aβ{sub 1-42} injected rat brains.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer's disease

Highlights: • Lixisenatide reduced amyloid plaques, neurofibrillary tangles and neuroinflammation. • Activiation of PKA-CREB and inhibition of p38-MAPK were the protective mechanisms. • Lixisenatide might have the potential to be developed as a novel therapy for AD. Type 2 diabetes mellitus (T2DM) has been identified as a high risk factor for Alzheimer's disease (AD). The impairment of insulin signaling has been found in AD brain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, normalises insulin signaling and acts as a neuroprotective growth factor. We have previously shown that the long-lasting GLP-1 receptor (GLP-1R) agonist lixisenatide plays an important role in memory formation, synaptic plasticity and cell proliferation of rats. In the follow-up study, we analysed the neuroprotective effect and mechanism of lixisenatide, injected for 60 days at 10 nmol/kg i.p. once daily in APP/PS1/tau female mice and C57BL/6J female mice (as control) aged 12 month. The results showed that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. The study demonstrated that GLP-1R agonists such as lixisenatide might have the potential to be developed as a novel therapy for AD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Parkinson's disease-associated mutant LRRK2 phosphorylates Rab7L1 and modifies trans-Golgi morphology

Highlights: • Rab7L1 is identified as a bona fide substrate of LRRK2. • Ser72 is a major in-cell phosphorylation site of Rab7L1. • Parkinson's-linked mutations in LRRK2 increase the Ser72 phosphorylation of Rab7L1. • Rab7L1 phosphorylation at Ser72 modifies the trans-Golgi morphology. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the major genetic cause of autosomal-dominantly inherited Parkinson's disease. LRRK2 is implicated in the regulation of intracellular trafficking, neurite outgrowth and PD risk in connection with Rab7L1, a putative interactor of LRRK2. Recently, a subset of Rab GTPases have been reported as substrates of LRRK2. Here we examine the kinase activity of LRRK2 on Rab7L1 in situ in cells. Phos-tag analyses and metabolic labeling assays revealed that LRRK2 readily phosphorylates Golgi-localized wild-type Rab7L1 but not mutant forms that are distributed in the cytoplasm. In vitro assays demonstrated direct phosphorylation of Rab7L1 by LRRK2. Subsequent screening using Rab7L1 mutants harboring alanine-substitution for every single Ser/Thr residue revealed that Ser72 is a major phosphorylation site, which was confirmed by using a phospho-Ser72-specific antibody. Moreover, LRRK2 pathogenic Parkinson mutants altogether markedly enhanced the phosphorylation at Ser72. The modulation of Ser72 phosphorylation in Rab7L1 resulted in an alteration of the morphology and distribution of the trans-Golgi network. These data collectively support the involvement of Rab7L1 phosphorylation in the LRRK2-mediated cellular and pathogenetic mechanisms.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Modulation of hyaluronan polymer size regulates proliferation of perimysial fibroblasts in thyroid eye disease

Highlights: • IGF-1 and PH20 modulate HA polymer size. • HA polymer size regulates fibroblast proliferation. • Mitogenic effect of HA is mediated by membrane potential alteration. In active thyroid eye disease (TED), the extraocular muscles feature excessive hyaluronan (HA) accumulation and increased fibroblast proliferation. To investigate the effects of HA on proliferation, we cultured perimysial fibroblasts from extraocular muscles of active TED patients, and adopted IGF-1 and PH20 as modulators for HA concentration and HA polymer size. Based on the results, IGF-1 increased HA concentration, promoted high molecular weight HA (HMW-HA) proportion and stimulated fibroblast proliferation. Hyaluronidase PH20 decreased HA concentration, but caused HMW-HA accumulation and exaggerating proliferation as well. Combined treatment with both reagents resulted in retention of low molecular weight HA (LMW-HA), and suppressed fibroblast proliferation. Pearson correlation demonstrated no significance between HA concentration and proliferation. Mitogenic investigation unveiled the stimulatory effects of HMW-HA via membrane depolarization and inhibitive effects of LMW-HA via membrane hyperpolarization. Our findings offer insights into the essential role of HA molecular weight during TED pathogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Lipidomic profiling of plasma samples from patients with mitochondrial disease

Highlights: • All 14 lysoPCs were dramatically decreased in MD patients. • Acylcarnitines, TGs, PIs, PEs, unsaturated lysoPEs and PCs were significantly increased in MD patients. • PI 38:6, lysoPCs (20:0, 19:0, 18:0, 17:0) may be potentially sensitive and specific biomarkers for MD. Mitochondrial disease (MD) is a rare mitochondrial respiratory chain disorder with a high mortality and extremely challenging to treat. Although genomic, transcriptomic, and proteomic analyses have been performed to investigate the pathogenesis of MD, the role of metabolomics in MD, particularly of lipidomics remains unclear. This study was undertaken to identify potential lipid biomarkers of MD. An untargeted lipidomic approach was used to compare the plasma lipid metabolites in 20 MD patients and 20 controls through Liquid Chromatography coupled to Mass Spectrometry. Volcano plot analysis was performed to identify the different metabolites. Receiver operating characteristic (ROC) curves were constructed and the area under the ROC curves (AUC) was calculated to determine the potentially sensitive and specific biomarkers. A total of 41 lipids were significantly different in MD patients and controls. ROC curve analysis showed the top 5 AUC values of lipids (phosphatidylinositols 38:6, lysoPC 20:0, 19:0, 18:0, 17:0) are more than 0.99. Multivariate ROC curve based exploratory analysis showed the AUC of combination of top 5 lipids is 1, indicating they may be potentially sensitive and specific biomarkers for MD. We propose combination of these lipid species may be more valuable in predicting the development and progression of MD, and this will have important implications for the diagnosis and treatment of MD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

TREM2 modulates microglia phenotypes in the neuroinflammation of Parkinson's disease

Highlights: • TREM2, Arginase-1 and proinflammatory cytokines increased in the midbrain of PD mice. • Knockdown of TREM2 in BV2 microglia exaggerated M1 microglial inflammatory responses. • TREM2 overexpression promoted M2 polarization and alleviated microglial inflammation. • TREM2 plays a crucial role in altering M1 microglia to M2 phenotype. Neuroinflammation and overactivated microglia underlies the pathogenesis of Parkinson's disease (PD). Furthermore, microglia could polarize into classic inflammatory M1 and immunosuppressive M2 phenotype. Thus, inhibiting the overactivated inflammatory M1 microglia by promoting the transformation of microglia to the protective M2 phenotype provides potential therapy for PD, but the mechanism that modulates microglia polarization remains unknown. Triggering receptor expressed on myeloid cells-2 (TREM2) is a recently identified immune receptor expressed by the microglia in the brain. Emerging evidence indicates that TREM2 enhances the phagocytosis function of microglia and suppress inflammation. Based on these evidence, we hypothesized that TREM2 might play a protective role through regulating microglia polarization. Here, we employ a lentiviral strategy to overexpress or suppress TREM2 on microglia and found that TREM2 was essential for M2 microglia polarization. Knockdown of TREM2 in BV2 microglia inhibited M2 polarization and lead to exaggeration of M1 microglial inflammatory responses, whereas overexpression of TREM2 promoted M2 polarization and alleviated microglial inflammation. We also observed that the TREM2 level was higher in the midbrain of PD mice, which was accompanied by an elevated level of Arginase-1 and increased proinflammatory cytokines, suggesting that TREM2 is an important factor in switching the microglia phenotypes. Taken together, these findings indicate that TREM2 plays a crucial role in altering the proinflammatory M1 microglia to M2 phenotype and has beneficial effects in the immune pathogenesis of PD.

60 APPLIED LIFE SCIENCES↗