Release of proteins via ion exchange from albumin-heparin microspheres

Albumin-heparin and albumin microspheres were prepared as ion exchange gels for the controlled release of positively charged polypeptides and proteins. The adsorption isotherms of chicken egg and human lysozyme, as model proteins, on microspheres were obtained. An adsorption isotherm of chicken egg lysozyme on albumin-heparin microspheres was linear until saturation was abruptly reached,\ud \ud The adsorption isotherms of human lysozyme at low and high ionic strength were typical of adsorption isotherms of proteins on ion exchange gels. The adsorption of human lysozyme on albumin-heparin and albumin microspheres fit the Freundlich equation suggesting heterogeneous binding sites. This was consistent with the proposed multivalent, electrostatic interactions between human lysozyme and negatively charged microspheres. Scatchard plots of the adsorption processes of human lysozyme on albumin-heparin and albumin microspheres suggested negative cooperativity, while positive cooperativity was observed for chicken egg lysozyme adsorption on albumin-heparin microspheres.\ud \ud Human lysozyme loading of albumin-heparin microspheres was 3 times higher than with albumin microspheres, with long term release occurring via an ion exchange mechanism. Apparent diffusion coefficients of 2.1 × 10-1 and 3.9 × 10-11cm2/sec were obtained for the release of human lysozyme from albumin-heparin and albumin microspheres, respectively. The release was found to be independent of diffusion, since the rate determining step was likely an adsorption/desorption processes. An apparent diffusion coefficient of 4.1 × 10-12 cm2/sec was determined for the release of chicken egg lysozyme from albumin-heparin microspheres.\ud \ud Low release of the lysozymes from albumin-heparin microspheres was observed in deionized water, consistent with the proposed ion exchange release mechanism. Overall, albumin-heparin microspheres demonstrated enhanced ion exchange characteristics over albumin microspheres

Release of macromolecules from albumin-heparin microspheres

Hydrophilic microspheres based on albumin-heparin conjugates have been prepared as a macromolecular delivery system. The soluble albumin-heparin conjugate was synthesized and crosslinked in a water-in-oil emulsion with glutaraldehyde to form microspheres in the same manner as for albumin microsphere preparation. The microspheres were characterized in terms of their size and swelling properties. The loading of macromolecules into albumin-heparin microspheres was carried out concurrently and after microsphere preparation. FITC-dextran was applied as a model macromolecule. A higher loading content was achieved when loading was carried out concurrently with microsphere preparation than when loaded subsequently. Prolonged release of FITC-dextran from albumin-heparin microspheres was achieved and attributed to the high molecular weight of the macromolecule. The release of FITC-dextran was modulated by crosslinking density, loading content and the method of drug incorporation. Apparently, the mechanism of FITC-dextran release from albumin-heparin microspheres was dependent on the method of drug incorporation. For release of FITC-dextran from the microspheres, assuming negligible interactions, a diffusion coefficient of 1.7 × 10¿9 cm2/s was determined

Interannual variability of winter-spring temperature in the Middle Atlantic Bight : relative contributions of atmospheric and oceanic processes

Author Posting. © American Geophysical Union, 2016. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Oceans 121 (2016): 4209–4227, doi:10.1002/2016JC011646.Relative contributions between the local atmospheric and oceanic processes on the interannual variability of winter-spring shelf temperature in the Middle Atlantic Bight (MAB) are investigated based on a regional ocean model. The model demonstrates sufficient capability to realistically simulate the interannual temperature changes during 2003–2014. On interannual time scales, the mean winter/spring temperature in the MAB is determined by the combination of the initial temperature at the beginning of the season and the mean cumulative air-sea flux, while the mean cumulative ocean advective flux plays a secondary role. In spite of the overall importance of air-sea flux in determining the winter and spring temperature, the relative contributions between air-sea flux and ocean advective flux on the evolution of the temperature anomaly in each individual year varies. The predictability of spring (April–June) temperature based on winter (January–March) temperature is weak because the temporal decorrelation time scale changes significantly from year to year. Both the highly variable shelf temperature and its decorrelation time scale are affected by the changes in the relative contributions between the air-sea flux and ocean advective flux.National Science Foundation Grant Number: OCE-14356022016-12-1

The role of atmospheric forcing versus ocean advection during the extreme warming of the Northeast U.S. continental shelf in 2012

Author Posting. © American Geophysical Union, 2015. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Oceans 120 (2015): 4324–4339, doi:10.1002/2014JC010547.In the coastal ocean off the Northeast U.S., the sea surface temperature (SST) in the first half of 2012 was the highest on the record for the past roughly 150 years of recorded observations. The underlying dynamical processes responsible for this extreme event are examined using a numerical model, and the relative contributions of air-sea heat flux versus lateral ocean advective heat flux are quantified. The model accurately reproduces the observed vertical structure and the spatiotemporal characteristics of the thermohaline condition of the Gulf of Maine and the Middle Atlantic Bight waters during the anomalous warming period. Analysis of the model results show that the warming event was primarily driven by the anomalous air-sea heat flux, while the smaller contribution by the ocean advection worked against this flux by acting to cool the shelf. The anomalous air-sea heat flux exhibited a shelf-wide coherence, consistent with the shelf-wide warming pattern, while the ocean advective heat flux was dominated by localized, relatively smaller-scale processes. The anomalous cooling due to advection primarily resulted from the along-shelf heat flux divergence in the Gulf of Maine, while in the Middle Atlantic Bight the advective contribution from the along-shelf and cross-shelf heat flux divergences was comparable. The modeling results confirm the conclusion of the recent analysis of in situ data by Chen et al. (2014a) that the changes in the large-scale atmospheric circulation in the winter of 2011–2012 primarily caused the extreme warm anomaly in the spring of 2012. The effect of along-shelf or cross-shelf ocean advection on the warm anomalies from either the Scotian Shelf or adjacent continental slope was secondary.K.C. was supported by the Woods Hole Oceanographic Institution Postdoctoral Scholar program, the Coastal Ocean Institute, and the National Science Foundation (NSF) under grant OCE-1435602. G.G.G. was supported by NSF grants OCE-1435602 and OCE-1129125. Y.-O.K. was supported by the NSF grant OCE-1435602. W.G.Z. was supported by the NSF grant OCE-1129125.2015-12-1

Preparation and characterization of microspheres of albumin-heparin conjugates

Albumin-heparin microspheres have been prepared as a new drug carrier. A soluble albumin-heparin conjugate was synthesized by forming amide bonds between human serum albumin and heparin. After purification the albumin-heparin conjugate was crosslinked in a water-in-oil emulsion to form albumin-heparin microspheres. The composition of the conjugate was determined by amino acid analysis. The swelling properties of albumin-heparin microspheres were investigated as a function of pH and ionic strength and compared with albumin microspheres. Albumin-heparin and albumin microspheres exhibited stimuli-sensitive swelling. Both microsphere systems exhibited low swelling at low pH and high swelling at higher pH caused by ionization of amino acids of serum albumin. The swelling of albumin-heparin microspheres was more sensitive toward ionic strength than that of albumin microspheres. This was due to the greater negative charge of the albumin-heparin microspheres. Surfaces of albumin-heparin and albumin microspheres were characterized by ESCA, contact angle measurements, electrophoresis, and scanning electron microscopy. Surface analysis indicated the presence of heparin at the albumin-heparin microsphere/water interface

Biodegradable PLGA Based Nanoparticles for Sustained Regional Lymphatic Drug Delivery

The purpose of this work is to evaluate biodegradable drug carriers with defined size, hydrophobicity, and surface charge density for preferential lymphatic uptake and retention for sustained regional drug delivery. PLGA–PMA:PLA-PEG (PP) nanoparticles of defined size and relative hydrophobicity were prepared by nanoprecipitation method. These were compared with PS particles of similar sizes and higher hydrophobicity. PLGA–PMA:PLGA-COOH (PC) particles at 80:20, 50:50, and 20:80 ratios were prepared by nanoprecipitation for the charge study. Particle size and zeta potential were characterized by dynamic light scattering and laser doppler anemometry, respectively. Particles were administered in vivo to rats subcutaneously. Systemic and lymph node uptake was evaluated by marker recovery. Lymphatic uptake and node retention of PP nanoparticles was shown to be inversely related to size. Lymphatic uptake and node retention of PP particles, as compared to PS particles, was shown to be inversely related to hydrophobicity. Lastly, lymphatic uptake and node retention of PC nanoparticles were directly related to the anionic charge on the particles. In vivo lymphatic uptake and retention in a rat model indicates that the 50 nm PP particles are ideal for sustained regional delivery into the lymphatics for prevention/treatment of oligometastases

A Cremophor-Free Formulation for Tanespimycin (17-AAG) using PEO-b-PDLLA Micelles: Characterization and Pharmacokinetics in Rats

Tanespimycin (17-allylamino-17-demethoxygeldanamycin or 17-AAG) is a promising heat shock protein 90 inhibitor currently undergoing clinical trials for the treatment of cancer. Despite its selective mechanism of action on cancer cells, 17-AAG faces challenging issues due to its poor aqueous solubility, requiring formulation with Cremophor EL (CrEL) or ethanol (EtOH). Therefore, a CrEL-free formulation of 17-AAG was prepared using amphiphilic diblock micelles of poly(ethylene oxide)-b-poly(D,L-lactide) (PEO-b-PDLLA). Dynamic light scattering revealed PEO-b-PDLLA (12:6 kDa) micelles with average sizes of 257 nm and critical micelle concentrations of 350 nM, solubilizing up to 1.5 mg/mL of 17-AAG. The area under the curve (AUC) of PEO-b-PDLLA micelles was 1.3-fold that of the standard formulation. The renal clearance (CLrenal) increased and the hepatic clearance (CLhepatic) decreased with the micelle formulation, as compared to the standard vehicle. The micellar formulation showed a 1.3-fold increase in the half-life (t1/2) of the drug in serum and 1.2-fold increase in t1/2 of urine. As expected, because it circulated longer in the blood, we also observed a 1.7-fold increase in the volume of distribution (Vd) with this micelle formulation compared to the standard formulation. Overall, the new formulation of 17-AAG in PEO-b-PDLLA (12:6 kDa) micelles resulted in a favorable 150-fold increase in solubility over 17-AAG alone, while retaining similar properties to the standard formulation. Our data indicates that the nanocarrier system can retain the pharmacokinetic disposition of 17-AAG without the need for toxic agents such as CrEL and EtOH

Long-term SST variability on the Northwest Atlantic continental shelf and slope

Author Posting. © American Geophysical Union, 2020. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 47(1), (2020): e2019GL085455, doi:10.1029/2019GL085455.The meridional coherence, connectivity, and regional inhomogeneity in long‐term sea surface temperature (SST) variability over the Northwest Atlantic continental shelf and slope from 1982–2018 are investigated using observational data sets. A meridionally concurrent large SST warming trend is identified as the dominant signal over the length of the continental shelf and slope between Cape Hatteras in North Carolina and Cape Chidley, Newfoundland and Labrador, Canada. The linear trends are 0.37 ± 0.06 and 0.39 ± 0.06 °C/decade for the shelf and slope regions, respectively. These meridionally averaged SST time series over the shelf and slope are consistent with each other and across multiple longer observational data sets with records dating back to 1900. The coherence between the long‐term meridionally averaged time series over the shelf and slope and basin‐wide averaged SST in the North Atlantic implies approximately two thirds of the warming trend during 1982–2018 may be attributed to natural climate variability and the rest to externally forced change including anthropogenic warming.We are grateful to the Editor Dr. Kathleen Donohue and two anonymous reviewers. This work was supported by NOAA's Climate Program Office's Modeling, Analysis, Predictions, and Projections (MAPP) program (NA19OAR4320074). We acknowledge our participation in MAPP's Marine Prediction Task Force. The data of NOAA OISST used in this study are available at NOAA Earth System Research Laboratory (https://www.esrl.noaa.gov/psd/data/gridded/data.noaa.oisst.v2.highres.html). The HadISST data set is available at Met Office, Hadley Centre (https://www.metoffice.gov.uk/hadobs/hadisst/). The COBE SST and NOAA ERSST data sets are available at NOAA Earth System Research Laboratory's Physical Sciences Division (https://www.esrl.noaa.gov/psd/data/gridded/data.cobe.html; https://www.esrl.noaa.gov/psd/data/gridded/data.noaa.ersst.v5.html). The near‐surface air temperature is available at Global Historical Climatology Network‐Monthly Database (https://www.ncdc.noaa.gov/data‐access/land‐based‐station‐data/land‐based‐datasets/global‐historical‐climatology‐network‐monthly‐version‐4). The data of SSH are available at Copernicus Marine Environment Monitoring Service (http://marine.copernicus.eu/services‐portfolio/access‐to‐products/?option=com_csw&view=details&product_id=SEALEVEL_GLO_PHY_ L4_REP_OBSERVATIONS_008_047).2020-07-0

Long-term follow-up results of endoscopic treatment of gastroesophageal reflux disease with the MUSE TM endoscopic stapling device

Background The initial 6-month data for MUSE™ (Medigus, Omer, Israel) endoscopic stapling device were reported (Zacherl et al. in Surg Endosc 29:220–229, 2015). The current study aims to evaluate the long-term clinical outcome of 37 patients who received endoscopic gastroesophageal reflux disease (GERD) treatment with the MUSE™ device. Methods Efficacy and safety data for 37 patients were analyzed at baseline, 6 months, and 4 years post-procedure. In one center (IU), efficacy and safety data were evaluated at baseline, 6 months post-procedure, and then annually up to 4 years. Results No new complications have been reported in our long-term analysis. The proportions of patients who remained off daily PPI were 83.8 % (31/37) at 6 months and 69.4 % (25/36) at 4 years post-procedure. GERD-Health Related Quality of Life (HRQL) scores (off PPI) were significantly decreased from baseline to 6 months and 4 years post-procedure. The daily dosage of GERD medications, measured as omeprazole equivalents (mean ± SD, mg), decreased from 66.1 ± 33.2 at baseline to 10.8 ± 15.9 at 6 months and 12.8 ± 19.4 at 4 years post-procedure (P < 0.01). Conclusions In our multi-center prospective study, the MUSE™ stapling device appears to be safe and effective in improving symptom scores as well as reducing PPI use in patients with GERD. These results appeared to be equal to or better than those of the other devices for endoluminal GERD therapy. Future studies with larger patient series, sham control group, and greater number of staples are awaited