Ultrashort echo time MRI of the lung in children and adolescents: comparison with non-enhanced computed tomography and standard post-contrast T1w MRI sequences.

OBJECTIVES: To compare the diagnostic value of ultrashort echo time (UTE) magnetic resonance imaging (MRI) for the lung versus the gold standard computed tomography (CT) and two T1-weighted MRI sequences in children. METHODS: Twenty-three patients with proven oncologic disease (14 male, 9 female; mean age 9.0 + / - 5.4 years) received 35 low-dose CT and MRI examinations of the lung. The MRI protocol (1.5-T) included the following post-contrast sequences: two-dimensional (2D) incoherent gradient echo (GRE; acquisition with breath-hold), 3D volume interpolated GRE (breath-hold), and 3D high-resolution radial UTE sequences (performed during free-breathing). Images were evaluated by considering image quality as well as distinct diagnosis of pulmonary nodules and parenchymal areal opacities with consideration of sizes and characterisations. RESULTS: The UTE technique showed significantly higher overall image quality, better sharpness, and fewer artefacts than both other sequences. On CT, 110 pulmonary nodules with a mean diameter of 4.9 + / - 2.9 mm were detected. UTE imaging resulted in a significantly higher detection rate compared to both other sequences (p < 0.01): 76.4% (84 of 110 nodules) for UTE versus 60.9% (67 of 110) for incoherent GRE and 62.7% (69 of 110) for volume interpolated GRE sequences. The detection of parenchymal areal opacities by the UTE technique was also significantly higher with a rate of 93.3% (42 of 45 opacities) versus 77.8% (35 of 45) for 2D GRE and 80.0% (36 of 45) for 3D GRE sequences (p < 0.05). CONCLUSION: The UTE technique for lung MRI is favourable in children with generally high diagnostic performance compared to standard T1-weighted sequences as well as CT. Key Points • Due to the possible acquisition during free-breathing of the patients, the UTE MRI sequence for the lung is favourable in children. • The UTE technique reaches higher overall image quality, better sharpness, and lower artefacts, but not higher contrast compared to standard post-contrast T1-weighted sequences. • In comparison to the gold standard chest CT, the detection rate of small pulmonary nodules small nodules ≤ 4 mm and subtle parenchymal areal opacities is higher with the UTE imaging than standard T1-weighted sequences.

Simultaneous Cross-Linking and Cross-Polymerization of Enzyme Responsive Polyethylene Glycol Nanogels in Confined Aqueous Droplets for Reduction of Low-Density Lipoprotein Oxidation.

A key initiating step in atherosclerosis is the accumulation and retention of apolipoprotein B complexing lipoproteins within the artery walls. In this work, we address this exact initiating mechanism of atherosclerosis, which results from the oxidation of low-density lipoproteins (oxLDL) using therapeutic nanogels. We present the development of biocompatible polyethylene glycol (PEG) cross-linked nanogels formed from a single simultaneous cross-linking and co-polymerization step in water without the requirement for an organic solvent, high temperature, or shear stress. The nanogel synthesis also incorporates in situ noncovalent electrostatically driven template polymerization around an innate anti-inflammatory and anti-oxidizing paraoxonase-1 (PON-1) enzyme payload-the release of which is triggered because of matrix metalloproteinase responsive elements instilled in the PEG cross-linker monomer. The results obtained demonstrate the potential of triggered release of the PON-1 enzyme and its efficacy against the production of ox-LDL, and therefore a reduction in macrophage foam cell and reactive oxygen species formation.

The Composition of Reconstituted High-Density Lipoproteins (rHDL) Dictates the Degree of rHDL Cargo- and Size-Remodeling via Direct Interactions with Endogenous Lipoproteins.

The application of reconstituted high-density lipoproteins (rHDL) as a drug-carrier has during the past decade been established as a promising approach for effective receptor-mediated drug delivery, and its ability to target tumors has recently been confirmed in a clinical trial. The rHDL mimics the endogenous HDL, which is known to be highly dynamic and undergo extensive enzyme-mediated remodulations. Hence, to reveal the physiological rHDL stability, a thorough characterization of the dynamics of rHDL in biologically relevant environments is needed. We employ a size-exclusion chromatography (SEC) method to evaluate the dynamics of discoidal rHDL in fetal bovine serum (FBS), where we track both the rHDL lipids (by the fluorescence from lipid-conjugated fluorophores) and apoA-I (by human apoA-I ELISA). We show by using lipoprotein depleted FBS and isolated lipoproteins that rHDL lipids can be transferred to endogenous lipoproteins via direct interactions in a nonenzymatic process, resulting in rHDL compositional- and size-remodeling. This type of dynamics could lead to misinterpretations of fluorescence-based rHDL uptake studies due to desorption of labile lipophilic fluorophores or off-target side effects due to desorption of incorporated drugs. Importantly, we show how the degree of rHDL remodeling can be controlled by the compositional design of the rHDL. Understanding the correlation between the molecular properties of the rHDL constituents and their collective dynamics is essential for improving the rHDL-based drug delivery platform. Taken together, our work highlights the need to carefully consider the compositional design of rHDL and test its stability in a biological relevant environment, when developing rHDL for drug delivery purposes.

Enhancing adoptive CD8 T cell therapy by systemic delivery of tumor associated antigens.

Adoptive T-cell transfer (ACT) offers a curative therapeutic option for subsets of melanoma and hematological cancer patients. To increase response rates and broaden the applicability of ACT, it is necessary to improve the post-infusion performance of the transferred T cells. The design of improved treatment strategies includes transfer of cells with a less differentiated phenotype. Such T cell subsets have high proliferative potential but require stimulatory signals in vivo to differentiate into tumor-reactive effector T cells. Thus, combination strategies are needed to support the therapeutic implementation of less differentiated T cells. Here we show that systemic delivery of tumor-associated antigens (TAAs) facilitates in vivo priming and expansion of previously non-activated T cells and enhance the cytotoxicity of activated T cells. To achieve this in vivo priming, we use flexible delivery vehicles of TAAs and a TLR7/8 agonist. Contrasting subcutaneous delivery systems, these vehicles accumulate TAAs in the spleen, thereby achieving close proximity to both cross-presenting dendritic cells and transferred T cells, resulting in robust T-cell expansion and anti-tumor reactivity. This TAA delivery platform offers a strategy to safely potentiate the post-infusion performance of T cells using low doses of antigen and TLR7/8 agonist, and thereby enhance the effect of ACT.

Ecosystem sentinels for climate change? Evidence of wetland cover changes over the last 30 years in the tropical Andes.

While the impacts of climate change on individual species and communities have been well documented there is little evidence on climate-mediated changes for entire ecosystems. Pristine alpine environments can provide unique insights into natural, physical and ecological response to climate change yet broad scale and long-term studies on these potential 'ecosystem sentinels' are scarce. We addressed this issue by examining cover changes of 1689 high-elevation wetlands (temporarily or perennial water-saturated grounds) in the Bolivian Cordillera Real, a region that has experienced significant warming and glacier melting over the last 30 years. We combined high spatial resolution satellite images from PLEIADES with the long-term images archive from LANDSAT to 1) examine environmental factors (e.g., glacier cover, wetland and watershed size) that affected wetland cover changes, and 2) identify wetlands' features that affect their vulnerability (using habitat drying as a proxy) in the face of climate change. Over the (1984-2011) period, our data showed an increasing trend in the mean wetland total area and number, mainly related to the appearance of wet grassland patches during the wetter years. Wetland cover also showed high inter-annual variability and their area for a given year was positively correlated to precipitation intensities in the three months prior to the image date. Also, round wetlands located in highly glacierized catchments were less prone to drying, while relatively small wetlands with irregularly shaped contours suffered the highest rates of drying over the last three decades. High Andean wetlands can therefore be considered as ecosystem sentinels for climate change, as they seem sensitive to glacier melting. Beyond the specific focus of this study, our work illustrates how satellite-based monitoring of ecosystem sentinels can help filling the lack of information on the ecological consequences of current and changing climate conditions, a common and crucial issue especially in less-developed countries.

Blood contamination and dentin bonding--effect of anticoagulant in laboratory studies.

OBJECTIVE: To investigate the influence of heparinized blood vs. native blood on the marginal adaptation of dentin bonded composite resin restorations. METHODS: Cylindrical dentin cavities were prepared in 40 extracted human incisors. After acid-etching four groups (n=10) were contaminated with either fresh capillary blood (FCB), heparinized venous blood (HPB), saline (SAL) or heparinized saline (HPS) and bonded and filled with Scotchbond 1/Z 100. After water storage for 21 days and thermocycling (2000 x, 5-55 degrees C), replicas were produced for evaluation of marginal adaptation by means of quantitative marginal analysis in the SEM. Statistical analysis was performed with the Kruskal-Wallis-test and the Bonferroni correction for multiple comparisons at p<0.05. RESULTS: There were no differences between groups SAL, HPS and HPB. Contamination with fresh capillary blood resulted in significantly higher amounts of marginal openings compared to all other groups. SIGNIFICANCE: Freshly drawn blood has to be used for blood contamination experiments in laboratory studies.