GdClean: removal of Gadolinium contamination in mass cytometry data.

MOTIVATION: Mass cytometry (Cytometry by Time-Of-Flight, CyTOF) is a single-cell technology that is able to quantify multiplex biomarker expressions and is commonly used in basic life science and translational research. However, the widely used Gadolinium (Gd)-based contrast agents (GBCAs) in magnetic resonance imaging (MRI) scanning in clinical practice can lead to signal contamination on the Gd channels in the CyTOF analysis. This Gd contamination greatly affects the characterization of the real signal from Gd-isotope-conjugated antibodies, severely impairing the CyTOF data quality and ruining downstream single-cell data interpretation. RESULTS: We first in-depth characterized the signals of Gd isotopes from a control sample that was not stained with Gd-labeled antibodies but was contaminated by Gd isotopes from GBCAs, and revealed the collinear intensity relationship across Gd contamination signals. We also found that the intensity ratios of detected Gd contamination signals to the reference Gd signal were highly correlated with the natural abundance ratios of corresponding Gd isotopes. We then developed a computational method named by GdClean to remove the Gd contamination signal at the single-cell level in the CyTOF data. We further demonstrated that the GdClean effectively cleaned up the Gd contamination signal while preserving the real Gd-labeled antibodies signal in Gd channels. All of these shed lights on the promising applications of the GdClean method in preprocessing CyTOF datasets for revealing the true single-cell information. AVAILABILITY AND IMPLEMENTATION: The R package GdClean is available on GitHub at https://github.com/JunweiLiu0208/GdClean. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Chromatographic behavior of six lanthanides on a centrifugal mixer-settler extractor cascade.

This work furthers the development of counter-current chromatography as an industrial separation process method. It was demonstrated that the industrial counter-current chromatography methods, in particular, for the separation groups of rare earth metals, can be implemented in a modified cascade of centrifugal mixer-settler extractors. The retention behavior of rare earth elements (samarium, europium, gadolinium, terbium, dysprosium and yttrium) on the pilot chromatographic unit consisting of 70 serially connected centrifugal mixer-settler extractors was experimentally studied under isocratic elution conditions using the mixture of 30 vol.% CyanexⓇ572 + 10 vol.% tributylphosphate in a hydrocarbon diluent as the stationary phase and aqueous nitric acid as the mobile phase. Theoretical analysis of experimental studies showed an acceptable agreement between the assumptions of the theory and experimental results.

Detection and imaging of gadolinium accumulation in human bone tissue by micro- and submicro-XRF.

Gadolinium-based contrast agents (GBCAs) are frequently used in patients undergoing magnetic resonance imaging. In GBCAs gadolinium (Gd) is present in a bound chelated form. Gadolinium is a rare-earth element, which is normally not present in human body. Though the blood elimination half-life of contrast agents is about 90 minutes, recent studies demonstrated that some tissues retain gadolinium, which might further pose a health threat due to toxic effects of free gadolinium. It is known that the bone tissue can serve as a gadolinium depot, but so far only bulk measurements were performed. Here we present a summary of experiments in which for the first time we mapped gadolinium in bone biopsy from a male patient with idiopathic osteoporosis (without indication of renal impairment), who received MRI 8 months prior to biopsy. In our studies performed by means of synchrotron radiation induced micro- and submicro-X-ray fluorescence spectroscopy (SR-XRF), gadolinium was detected in human cortical bone tissue. The distribution of gadolinium displays a specific accumulation pattern. Correlation of elemental maps obtained at ANKA synchrotron with qBEI images (quantitative backscattered electron imaging) allowed assignment of Gd structures to the histological bone structures. Follow-up beamtimes at ESRF and Diamond Light Source using submicro-SR-XRF allowed resolving thin Gd structures in cortical bone, as well as correlating them with calcium and zinc.

Practical aspects of 153Gd as a radioactive source for use in brachytherapy.

The goal of this study was to investigate the production, purification and immobilization techniques for a 153Gd brachytherapy source. We have investigated the maximum attainable specific activity of 153Gd through the irradiation of Gd2O3 enriched to 30.6% 152Gd at McMaster Nuclear Reactor. The advantage of producing 153Gd through this production pathway is the possibility to irradiate pre-sealed pellets of 152Gd enriched Gd2O3, thereby removing the need to perform chemical separation with large quantities of radio-impurities. However, small amounts of long-lived impurities are produced from the irradiation of enriched 152Gd targets due to traces of Eu in the sample. If the amount of impurities produced is deemed unacceptable, 153Gd can be isolated as an aqueous solution, chemically separated from impurities and loaded onto a sorbent with a high affinity for Gd before encapsulation.

Gadolinium-uptake by aquatic and terrestrial organisms-distribution determined by laser ablation inductively coupled plasma mass spectrometry.

Gadolinium (Gd) based contrast agents (CA) are used to enhance magnetic resonance imaging. As a consequence of excretion by patients and insufficient elimination in wastewater treatment plants they are detected in high concentrations in surface water. At present, little is known about the uptake of these species by living organisms in aquatic systems. Therefore the uptake of gadolinium containing chelates by plants and animals grown in exposed water or on soil irrigated with exposed water was investigated. For this purpose two types of plants were treated with two different contrast agents. The uptake of the Gd contrast agents was studied by monitoring the elemental distribution with laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). This technique allows the multi-elemental analysis of solid samples with high resolution and little sample preparation. The analysis of L. minor showed that the uptake of Gd correlated with the concentration of gadodiamide in the water. The higher the concentration in the exposed water, the larger the Gd signal in the LA-ICP-MS acquired image. Exposure time experiments showed saturation within one day. The L. minor had contact with the CAs through roots and fronds, whereas the L. sativum only showed uptake through the roots. These results show that an external absorption of the CA through the leaves of L. sativum was impossible. All the analyzed parts of the plant showed Gd signal from the CA; the highest being at the main vein of the leaf. It is shown that the CAs can be taken up from plants. Furthermore, the uptake and distribution of Gd in Daphnia magna were shown. The exposure via cultivation medium is followed by Gd signals on the skin and in the area of the intestine, while the uptake via exposed nutrition algae causes the significantly highest Gd intensities in the area of the intestine. Because there are hints of negative effects for human organism these findings are important as they show that Gd based CAs may reach the human food chain via plants and animals growing in contaminated water or plants growing in fields which are irrigated with surface water.

Multi-objective optimization of chromatographic rare earth element separation.

The importance of rare earth elements in modern technological industry grows, and as a result the interest for developing separation processes increases. This work is a part of developing chromatography as a rare earth element processing method. Process optimization is an important step in process development, and there are several competing objectives that need to be considered in a chromatographic separation process. Most studies are limited to evaluating the two competing objectives productivity and yield, and studies of scenarios with tri-objective optimizations are scarce. Tri-objective optimizations are much needed when evaluating the chromatographic separation of rare earth elements due to the importance of product pool concentration along with productivity and yield as process objectives. In this work, a multi-objective optimization strategy considering productivity, yield and pool concentration is proposed. This was carried out in the frame of a model based optimization study on a batch chromatography separation of the rare earth elements samarium, europium and gadolinium. The findings from the multi-objective optimization were used to provide with a general strategy for achieving desirable operation points, resulting in a productivity ranging between 0.61 and 0.75 kgEu/mcolumn(3), h(-1) and a pool concentration between 0.52 and 0.79 kgEu/m(3), while maintaining a purity above 99% and never falling below an 80% yield for the main target component europium.

Facile and highly efficient removal of trace Gd(III) by adsorption of colloidal graphene oxide suspensions sealed in dialysis bag.

A facile, highly efficient and second-pollution-free strategy to remove trace Gd(III) from aqueous solutions by adsorption of colloidal graphene oxide (GO) suspensions in dialysis bag has been developed. The effects of pH, ionic strength and temperature on Gd(III) adsorption, and the pH-dependent desorption were investigated. The maximum adsorption capacity of Gd(III)on GO at pH=5.9±0.1 and T=303K was 286.86mgg(-1), higher than any other currently reported. The Gd(III)-saturated GO suspension could resume colloidal state in 0.1M HNO3 with desorption rate of 85.00% in the fifth adsorption-desorption cycle. Gd(III) adsorption rate on GO was dependent more on pH and ionic strength than on temperature. The abundant oxygen-containing functional groups such as carboxyl and hydroxyl played a vital role on adsorption. The thermodynamics and kinetics investigations revealed that the adsorption of Gd(III) on GO was an endothermic, spontaneous and monolayer absorption process, which well fitted the pseudo-second-order model. GO could be a promising adsorbent applied in the enrichment and removal of lanthanides from aqueous solutions. More significantly, the combination of colloidal GO suspension with dialysis membrane facilely solves the re-pollution of the treated solutions due to the great difficulties in separation and recovery of GO.

Experimental productivity rate optimization of rare earth element separation through preparative solid phase extraction chromatography.

Separating individual rare earth elements from a complex mixture with several elements is difficult and this is emphasized for the middle elements: Samarium, Europium and Gadolinium. In this study we have accomplished an overloaded one-step separation of these rare earth elements through preparative ion-exchange high-performance liquid chromatography with an bis (2-ethylhexyl) phosphoric acid impregnated column and nitric acid as eluent. An inductively coupled plasma mass spectrometry unit was used for post column element detection. The main focus was to optimize the productivity rate, subject to a yield requirement of 80% and a purity requirement of 99% for each element, by varying the flow rate and batch load size. The optimal productivity rate in this study was 1.32kgSamarium/(hmcolumn(3)), 0.38kgEuropium/(hmcolumn(3)) and 0.81kgGadolinium/(hmcolumn(3)).

A non-aqueous reduction process for purifying ¹5³Gd produced in natural europium targets.

Gadolinium-153 is a low-energy gamma-emitter used in nuclear medicine imaging quality assurance. Produced in nuclear reactors using natural Eu2O3 targets, ¹5³Gd is radiochemically separated from europium isotopes by europium reduction. However, conventional aqueous europium reduction produces hydrogen gas, a flammability hazard in radiological hot cells. We altered the traditional reduction method, using methanol as the process solvent to nearly eliminate hydrogen gas production. This new, non-aqueous reduction process demonstrates greater than 98% europium removal and gadolinium yields of 90%.

Speciation of gadolinium in surface water samples and plants by hydrophilic interaction chromatography hyphenated with inductively coupled plasma mass spectrometry.

Hydrophilic interaction chromatography (HILIC) coupled with inductively coupled plasma mass spectrometry (ICP-MS) was optimized for speciation analysis of gadolinium-based contrast agents in environmental samples, in particular surface river waters and plants. Surface water samples from the Teltow channel, near Berlin, were investigated over a distance of 5 km downstream from the influx of a wastewater treatment plant. The total concentration of gadolinium increased significantly from 50 to 990 ng L(-1) due to the influx of the contrast agents. After complete mixing with the river water, the concentration remained constant over a distance of at least 4 km. Two main substances [Dotarem(®) (Gd-DOTA) and Gadovist(®) (Gd-BT-DO3A)] have been identified in the river water using standards. A gadolinium-based contrast agent, possibly Gd-DOTA (Dotarem(®)), was also detected in water plant samples taken from the Teltow channel. Therefore, uptake of contrast agents [Gadovist(®) (Gd-BTDO3A), Magnevist(®) (Gd-DTPA), Omniscan(®) (Gd-DTPA-BMA), Dotarem(®) (Gd-DOTA), and Multihance(®) (Gd-BOPTA)] by plants was investigated in a model experiment using Lepidium sativum (cress plants). HILIC-ICP-MS was used for identification of different contrast agents, and a first approach for quantification using aqueous standard solutions was tested. For speciation analysis, all investigated contrast agents could be extracted from the plant tissues with a recovery of about 54 % for Multihance(®) (Gd-BOPTA) up to 106 % for Gadovist(®) (Gd-BT-DO3A). These experiments demonstrate that all contrast agents investigated are transported from the roots to the leaves where the highest content was measured.

Novel sorbents for removal of gadolinium-based contrast agents in sorbent dialysis and hemoperfusion: preventive approaches to nephrogenic systemic fibrosis.

Many forms of organocomplexed gadolinium (Gd) contrast agents have recently been linked to a debilitating and a potentially fatal skin disease called nephrogenic systemic fibrosis (NSF) in patients with renal failure. Free Gd released from these complexes via transmetallation is believed to be the most important trigger for NSF. In this work, nanostructure silica materials that have been functionalized with 1-hydroxy-2-pyridinone (1,2-HOPO-SAMMS) have been evaluated for selective and effective removal of both free and chelated Gd (gadopentetate dimeglumine and gadodiamide) from dialysate and blood. 1,2-HOPO SAMMS has high affinity, rapid removal rate, and large sorption capacity for both free and chelated Gd, properties that are far superior to those of activated carbon and zirconium phosphate currently used in the state-of-the-art sorbent dialysis and hemoperfusion systems. The SAMMS-based sorbent dialysis and hemoperfusion will potentially provide an effective and predicable strategy for removing the Gd from patients with impaired renal function after Gd exposure, thus allowing for the continued use of Gd-based contrast magnetic resonance imaging while removing the risk of NSF. FROM THE CLINICAL EDITOR: Chelated gadolinium (Gd) contrast agents have been linked to a debilitating disease called nephrogenic systemic fibrosis (NSF) in patients with renal failure. Free Gd+(3) released from the contrast agents is believed to be the trigger for NSF. In this work, functionalized nanostructured silica materials were evaluated for removal of both free and chelated gadolinium both from dialysate and blood. The new method demonstrated a rapid removal rate and large sorption capacity, and overall was far superior to currently used state-of-the-art sorbent dialysis and hemoperfusion systems.

Removal of gadolinium by dialysis: review of different strategies and techniques.

Nephrogenic systemic fibrosis (NSF) has been related to the administration of gadolinium-based contrast agents for magnetic resonance imaging studies in patients with kidney disease. After reviewing the pathophysiology of NSF, we discuss the possible factors contributing to the toxicity of gadolinium in susceptible patients, including the excessive amounts of intravenous iron and erythropoietin as well as the inflammatory states commonly seen in patients treated with hemodialysis. Since free gadolinium is the most accepted risk factor for NSF, we provide some suggestions to improve clearance of both free and chelated gadolinium using different dialysis strategies and techniques. J. Magn. Reson. Imaging 2009;30:1347-1349. (c) 2009 Wiley-Liss, Inc.

Modeling of gadolinium recovery from nitrate medium with 8-hydroxyquinoline by emulsion liquid membrane.

The extraction equilibrium of Gd(III) from nitrate medium by 8-hydroxyquinoline (HOX) in toluene was studied. Liquid-liquid investigations were first carried out. Based on the equilibrium results, the extraction of Gd(III) from aqueous nitrate medium into an emulsion liquid membrane system (ELM) containing 8-hydroxyquinoline in toluene as extractant, HNO(3) as stripping solution, Span-80 as surfactant was studied. The stability of the prepared ELM was studied in terms of the degree of membrane breakage. The different parameters affecting the permeation of gadolinium (III) were also studied. A general permeation model for the recovery of Gd(III) by the selected membrane is presented. The internal mass transfer in the water in oil (W/O) emulsion drop, the external mass transfer around the drop, the rates of formation and decomposition of the complex at the external aqueous-organic interface were considered.

Detailed study on simultaneous separation of rare earth elements by capillary electrophoresis.

Separation of all rare earth elements (REEs) by capillary zone electrophoresis was investigated in a system of alpha-hydroxyisobutyric acid (HIBA) as a main complex reagent and acetic acid (HAc) as an assistant complex reagent. In the combined system, ligand Ac- plays an important role in improving separation of Eu and Gd, and Y and Dy. The calculated ratio of Ac- to HIB- concentrations was compared and demonstrated that Eu and Gd, and Y and Dy tend to be separated at lower, and higher ratio of the two free ligands, respectively. An operational buffer system was developed for a complete separation of all REE ions.

The effect of mobile phase modifiers on the simultaneous LC elution of a gadolinium complex and free ligand.

A liquid chromatographic method was developed for simultaneous separation of a gadolinium complex and corresponding ligand using a reversed-phase anion-exchange column. The effect of mobile phase pH, EDTA and chloride ion concentration, added to the mobile phase as counter-ions, on the elution of a metal complex and ligand were investigated. Decreasing the mobile phase pH from 9.4 to 7.4 decreased the retention time of the free ligand but had little effect on changing the retention time of the complex. Increasing the EDTA concentration of the mobile phase from 0 to 0.5 mM decreased the retention of the free ligand but had little effect on changing the retention time of the metal complex. Both the retention times of the metal complex and free ligand decreased as the chloride ion concentration was increased from 0 to 0.2 M.