A billion-year shift in the formation of Earth's largest ore deposits.

Banded iron formations (BIFs) archive the relationship between Earth's lithosphere, hydrosphere, and atmosphere through time. However, constraints on the origin of Earth's largest ore deposits, hosted by BIFs, are limited by the absence of direct geochronology. Without this temporal context, genetic models cannot be correlated with tectono-thermal and atmospheric drivers responsible for BIF upgrading through time. Utilizing in situ iron oxide U-Pb geochronology, we provide a direct timeline of events tracing development of all the giant BIF-hosted hematite deposits of the Hamersley Province (Pilbara Craton, Western Australia). Direct dating demonstrates that the major iron ore deposits in the region formed during 1.4 to 1.1 Ga. This is one billion to hundreds of millions of years later than previous age constraints based upon 1) the presence of hematite ore clasts in conglomerate beds deposited before ~1.84 Ga, and 2) phosphate mineral dating, which placed the onset of iron mineralization in the Province at ~2.2 to 2.0 Ga during the great oxidation event. Dating of the hematite clasts verified the occurrence of a ~2.2 to 2.0 Ga event, reflecting widespread, but now largely eroded iron mineralization occurring when the Pilbara and Kaapvaal cratons were proximal. No existing phosphate mineral dates overlap with obtained hematite dates and therefore cannot be related to hematite crystallization and ore formation. New geochronology conclusively links all major preserved hematite deposits to a far younger (1.4 to 1.1 Ga) formation period, correlated with the amalgamation of Australia following breakup of the Columbia supercontinent.

Metallomic mapping of gut and brain in heavy metal exposed earthworms: A novel paradigm in ecotoxicology.

This study explored the uptake of lead in the epigeic earthworm Dendrobaena veneta exposed to 0, 1000, and 2500 µg Pb/g soil. The soil metal content was extracted using strong acid digestion and water leaching, and analysed by means of Inductively Coupled Plasma Mass Spectrometry (ICP-MS) to estimate absolute and bioavailable concentrations of metals in the soil. The guts and heads of lead-exposed earthworms were processed into formalin-fixed and paraffin embedded sections for high-resolution multi-element metallomic imaging via Laser Ablation ICP-MS (LA-ICP-MS). Metallomic maps of phosphorus, zinc, and lead were produced at 15-µm resolution in the head and gut of D. veneta. Additional 4-µm resolution metallomic maps of the earthworm brains were taken, revealing the detailed localisation of metals in the brain. The Pb bioaccumulated in the chloragogenous tissues of the earthworm in a dose-dependent manner, making it possible to track the extent of soil contamination. The bioaccumulation of P and Zn in earthworm tissues was independent of Pb exposure concentration. This approach demonstrates the utility of LA-ICP-MS as a powerful approach for ecotoxicology and environmental risk assessments.

Immunolabelling perturbs the endogenous and antibody-conjugated elemental concentrations during immuno-mass spectrometry imaging.

Immuno-mass spectrometry imaging uses lanthanide-conjugated antibodies to spatially quantify biomolecules via laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). The multi-element capabilities allow for highly multiplexed analyses that may include both conjugated antibodies and endogenous metals to reveal relationships between disease and chemical composition. Sample handling is known to perturb the composition of the endogenous elements, but there has been little investigation into the effects of immunolabelling and coverslipping. Here, we used cryofixed muscle sections to examine the impact of immunolabelling steps on the concentrations of a Gd-conjugated anti-dystrophin primary antibody, and the endogenous metals Cu and Zn. Primary antibody incubation resulted in a decrease in Zn, and an increase in Cu. Zn was removed from the cytoplasm where it was hypothesised to be more labile, whereas concentrated locations of Zn remained in the cell membrane in all samples that underwent the immunostaining process. Cu increased in concentration and was found mostly in the cell membrane. The concentration of the Gd-conjugated antibody when compared to the standard air-dried sample was not significantly different when coverslipped using an organic mounting medium, whereas use of an aqueous mounting medium significantly reduced the concentration of Gd. These results build on the knowledge of how certain sample handling techniques change elemental concentrations and distributions in tissue sections. Immunolabelling steps impact the concentration of endogenous elements, and separate histological sections are required for the quantitative analysis of endogenous elements and biomolecules. Additionally, coverslipping tissue sections for complementary immunohistochemical/immunofluorescent imaging may compromise the integrity of the elemental label, and organic mounting media are recommended over aqueous mounting media.

One-point calibration and matrix-matching concept for quantification of potentially toxic elements in wood by LA-ICP-MS.

The aim of this work is to evaluate two quantitative methods, based on the external calibration applied in laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) analysis, known as (i) analytical curve and (ii) one-point calibration, using the concept of matrix matching to quantify three potentially toxic elements (PTEs) in wood samples. These can biologically register changes in the abiotic environment and be applied to monitoring climate change or environmental toxicity. In this case, standard sample preparation was evaluated to prepare the standard pellets using Pinus taeda species as a matrix-matching concept. Six pellets of P. taeda, with different Pb, Cd, and Ba concentrations, were prepared to build the analytical curve and one-point calibration strategies. The LA-ICP-MS parameters were optimised for 206Pb, 208Pb, 112Cd, 114Cd, 137Ba, and 138Ba isotope analysis in wood samples. The two calibration strategies provided 74-110% analytical recovery from certified reference materials and similar results to those obtained by ICP-MS through the acid digestion of environmental wood samples from São Paulo City (Brazil). This demonstrated the applicability of the one-point calibration strategy in quantifying PTEs in wood samples, which could be used with environmental analyses. Differences observed between the Ba isotope results obtained via LA-ICP-MS and ICP-MS quantification were related to sampling by LA-ICP-MS and the ICP-MS sample introduction, as well as to laser matrix and transport effects because of the difference between the wood species evaluated.

A frozen suspension external calibration strategy for elemental quantitative imaging of fresh plant soft tissues by LA-ICP-MS with cryogenic ablation cell.

A simple and reliable external calibration strategy of LA-ICP-MS for fresh plant soft tissues was developed. The prepared plant suspension was frozen by the designed cryogenic ablation cell and used as external standard for quantitative elemental imaging analysis of fresh plant tissues. The controllable water content of the prepared external standards provides a similar matrix with fresh soft tissues, and a homogeneous elemental distribution could be ensured due to the fine grinding particle sizes. More interestingly, the presence of water increased the signal intensity produced by the suspension by a factor of 1.6 (Pb) to 66.6 (La) compared to that of the pressed cake. The excellent dispersing property and advantage of long-term use were achieved owing to the employment of 0.1% PAANa as suspending agent. A series of plant reference materials were analyzed, and the relative errors of most elements were less than 10 %, indicating that there is a reliable accuracy of the proposed method. The limits of detection (LODs) ranged from 0.1 ng·g-1 (La) to 1279 ng·g-1 (S). This method was used for elemental imaging analysis in rice leaves under arsenic stress, and the results were consistent with previous studies, which mean that the proposed method could provide technical support for researchers in the fields of agriculture and environment.

Spatial distribution of trace metals and associated transport proteins during bacterial infection.

Innate immune systems alter the concentrations of trace elements in host niches in response to invading pathogens during infection. This work reports the interplay between d-block metal ions and their associated biomolecules using hyphenated elemental techniques to spatially quantify both elemental distributions and the abundance of specific transport proteins. Here, lung tissues were collected for analyses from naïve and Streptococcus pneumoniae-infected mice fed on a zinc-restricted or zinc-supplemented diet. Spatiotemporal distributions of manganese (55Mn), iron (56Fe), copper (63Cu), and zinc (66Zn) were determined by quantitative laser ablation-inductively coupled plasma-mass spectrometry. The murine transport proteins ZIP8 and ZIP14, which are associated with zinc transport, were also imaged by incorporation of immunohistochemistry techniques into the analytical workflow. Collectively, this work demonstrates the potential of a single instrumental platform suitable for multiplex analyses of tissues and labelled antibodies to investigate complex elemental interactions at the host-pathogen interface. Further, these methods have the potential for broad application to investigations of biological pathways where concomitant measurement of elements and biomolecules is crucial to understand the basis of disease and aid in development of new therapeutic approaches.

Micro-distribution of arsenic in toenail clippings using laser ablation inductively coupled plasma mass spectrometry: implications for biomonitoring.

Toenails are a common monitoring tool for arsenic exposure, but the risk of external contamination of toenails has cast doubt on its usefulness. The main objective of this study is to investigate the micro-distribution of arsenic through the dorsoventral plane of nail clippings to understand endogenous vs exogenous sources. We used laser-ablation inductively coupled plasma mass spectrometry to measure arsenic through a dorsoventral cross-section of the nail plate collected from reference (N = 17) and exposed individuals (N = 35). Our main results showed (1) bulk toenail concentrations measured using ICP-MS in this study ranged from 0.54 to 4.35 µg/g; (2) there was a double-hump pattern in arsenic concentrations, i.e., dorsal and ventral layers had higher arsenic than the inner layer; (3) the double-hump was more pronounced in the exposed group (ventral: 6.25 µg/g; inner: 0.75 µg/g; dorsal: 0.95 µg/g) than the reference group (ventral: 0.58 µg/g; inner: 0.15 µg/g; dorsal: 0.29 µg/g) on average; (4) the distribution was, in part, associated with different binding affinity of nail layers (i.e., ventral > dorsal > inner); (5) most individuals in the higher exposure group showed > 25% contamination in ventral and dorsal nail layers; and (6) there were no statistically significant correlations between LA-ICP-MS arsenic with either bulk toenail arsenic or urine arsenic from the same individuals. Our results on micro-distribution and binding affinity provide insight into the impact of external contamination on arsenic concentrations and show how LA-ICP-MS can access the protected inner nail layer to provide a more accurate result.

In vitro and in vivo accumulation of the anticancer Ru complexes [RuII(cym)(HQ)Cl] and [RuII(cym)(PCA)Cl]Cl.

The cellular accumulation and the underlying mechanisms for the two ruthenium-based anticancer complexes [RuII(cym)(HQ)Cl] 1 (cym = η6-p-cymene, HQ = 8-hydroxyquinoline) and [RuII(cym)(PCA)Cl]Cl 2 (PCA = N-fluorophenyl-2-pyridinecarbothioamide) were investigated in HCT116 human colorectal carcinoma cells. The results showed that the cellular accumulation of both complexes increased over time and with higher concentrations, and that 2 accumulates in greater quantities in cells than 1. Inhibition studies of selected cellular accumulation mechanisms indicated that both 1 and 2 may be transported into the cells by both passive diffusion and active transporters, similar to cisplatin. Efflux experiments indicated that 1 and 2 are subjected to efflux through a mechanism that does not involve p-glycoprotein, as addition of verapamil did not make any difference. Exploring the influence of the Cu transporter by addition of CuCl2 resulted in a higher accumulation of 1 and 2 whilst the amount of Pt detected was slightly reduced when cells were treated with cisplatin. Complexes 1 and 2 were further explored in zebrafish where accumulation and distribution were determined with ICP-MS and LA-ICP-MS. The results correlated with the in vitro observations and zebrafish treated with 2 showed higher Ru contents than those treated with 1. The distribution studies suggested that both complexes mainly accumulated in the intestines of the zebrafish.

Effect of metabolic rate on time-lag changes in otolith microchemistry: an experimental approach using Salmo trutta.

Ecologists have long been interested in relevant techniques to track the field movement patterns of fish. The elemental composition of otoliths represents a permanent record of the growing habitats experienced by a fish throughout its lifetime and is increasingly used in the literature. The lack of a predictive and mechanistic understanding of the individual kinematics underlying ion incorporation/depletion limits our fine-scale temporal interpretation of the chemical signal recorded in the otolith. In particular, the rate at which elements are incorporated into otoliths is hypothesized to depend on fish physiology. However, to date, time lags have mostly been quantified on a population scale. Here, we report results from controlled experiments (translocation and artificially enriched environment) on individual trace element incorporation/depletion rates in Salmo trutta (Salmonidae). We reported significant lags (i.e. weeks to months) between changes in water chemistry and the subsequent change in otolith composition and highlighted substantial inter-individual variations in the timing and magnitude of Sr/Ca and Ba/Ca responses. These differences are partially linked to the energetic status (i.e. metabolic rate) of the individuals. It therefore appears that individuals with the highest metabolic rate are more likely to record detailed (i.e. brief) temporal changes than individuals having lower metabolic values. The time taken for environmental changes to be reflected in the growing otolith thus can no longer be assumed to remain a constant within populations. Results from the current study are a step towards the fine reconstruction of environmental histories in dynamic environments.

Multi-element imaging of urinary stones by LA-ICP-MS with a homogeneous co-precipitation CaC2O4-matrix calibration standard.

Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) studies on trace element concentration and their spatial distribution in CaC2O4-matrix urinary stones are important but powerfully rely on matrix-matched external calibration. In this work, CaC2O4 precipitate CaOx-1 which was doped with Mg, Cr, Mn, Fe, Co, Cu, Zn, and Sr was prepared by the homogeneous co-precipitation method. It had a homogeneous distribution of major (RSD of 0.46%) and trace elements (RSD of 1.83-6.92%) due to the negligible concentration difference compared with that prepared by the heterogeneous co-precipitation method. Based on this, an analytical method for quantitative determination of elemental concentration in CaC2O4-matrix samples was established using CaOx-1 as a calibration standard, and the accuracy of this method was assessed by calibrating the elemental concentration in another synthetic CaC2O4 precipitate CaOx-2 with relative deviation (Dr) from - 11.43% (Mn) to 9.76% (Mg). Finally, a methodology for quantitative imaging of Mg, Cr, Mn, Fe, Co, Cu, Zn, and Sr in urinary stones via LA-ICP-MS was developed. From the elemental distributional maps, an annular texture can be found for Mg, Cu, Zn, and Sr, which corresponds to the annular white and brown texture in the real urinary stone. A homogeneous distribution of Fe and low concentrations of Cr and Co were found throughout the stone, while Mn was highly concentrated in the margin of the stone. All these results demonstrate that quantitative distribution patterns of Mg, Cr, Mn, Fe, Co, Cu, Zn, and Sr can be obtained by LA-ICP-MS using CaOx-1 as a calibration standard, which can provide potential evidence for urological and other medical studies.

Direct multi-elemental analysis of cerebrospinal fluid samples by LA-ICP-MS employing an aerosol local extraction cryogenic ablation cell.

A novel method for direct high-throughput analysis of multi-elements in cerebrospinal fluid (CSF) samples by laser ablation inductively coupled plasma mass spectrometry with an aerosol local extraction cryogenic ablation cell (ALEC-LA-ICP-MS) was developed. Microliter-level CSF samples were frozen by a designed cryogenic ablation cell and directly analyzed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) without time-consuming pretreatment. Compared with the precision obtained at room temperature (20℃), that obtained at low temperature (- 25℃) was significantly improved; the RSDs were reduced from 8.3% (Zn) to 32.6% (Mn) to 2.2% (Pb) to 6.5% (Mn) with six times parallel determination. To meet the analytical requirement of the micro-volume CSF samples, the laminar flow aerosol local extraction strategy was adopted to improve the transmission efficiency of aerosols, and the signal intensity was increased by four times compared with the standard commercial ablation cell. The standard solution with 0.4% bovine serum albumin (BSA) matrix was used as matrix-match external standard, and Rh was added into the samples as internal standard. The limits of detection (LODs) ranged from 0.17 µg·L-1 (Mn) to 8.67 µg·L-1 (Mg). Standard addition recovery experiments and the determination of CRM serum L-1 and L-2 were carried out to validate the accuracy of the method; all results indicated there were excellent accuracy and precision in the proposed method. The matrix-scanning function in the GeoLas software combined with the microwell plate realizes the high-throughput automatic analysis. Twenty-four CSF samples from different patients were determined; the results showed that there might be a correlation between the metal elements in CSF and the diseases, which means that the proposed method has potential in the diagnosis of neurological diseases.

Comparative Analysis of Guatemalan and Qing Dynasty Jadeite Elemental Signs.

Different jadeites have different characteristics. In this paper, the La-ICP-MS test is used to compare and analyze the elemental characteristics of jadeite in Guatemala and the Qing dynasty. The test results show that the highest value of Guatemalan jadeite Ca can reach 2.5 apfu, while the highest value of Qing dynasty jadeite is 0.73 apfu. The highest value of Na is the same for both. The concentration distribution range and highest value of Guatemalan jadeite and Qing dynasty jadeite Mg/(Mg + Fe) are the same. Guatemalan jadeite and Qing dynasty jadeite have a very wide content of trace elements. Qing dynasty Ca/(Mg + Fe) distribution is wider. Concentrations of Guatemalan and Qing dynasty jadeite Sr/Ba, which is a marine sediment, are greater than 1. The Ba in the Qing dynasty jadeite sediments contains a large amount of clay, resulting in higher levels than the average amount in Guatemalan jadeite Ba. The standard distribution map is similar, showing a "horn" shape. The Sr distribution is uneven. Guatemalan jadeite is heavily enriched in rare earths. Eu shows positive and negative abnormalities. The total rare earth value is 8.15 ppm. Qing Dynasty jadeite shows light rare earth enrichment, and Eu is a positive anomaly. The total rare earth value is 7.07 ppm. The characteristics of the two elements are somewhat similar, but different, which does not rule out the possibility that Qing dynasty jadeite came from Guatemala.

Tackling the Challenging Determination of Trace Elements in Ultrapure Silicon Carbide by LA-ICP-MS.

The goal of accurately quantifying trace elements in ultrapure silicon carbide (SiC) with a purity target of 5N (99.999% purity) was addressed. The unsuitability of microwave-assisted acid digestion followed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis was proved to depend mainly on the contamination induced by memory effects of PTFE microwave vessels and by the purity levels of acids, even if highly pure ones were used in a clean environment. A new analytical protocol for the direct analysis of the solid material by laser ablation coupled with ICP-MS (LA-ICP-MS) was then exploited. Different samples were studied; the best results were obtained by embedding SiC (powders or grains) in epoxy resin. This technique has the great advantage of avoiding any source of external contamination, as grinding, pressing and sintering pretreatments are totally unnecessary. Two different laser wavelengths (266 and 193 nm) were tested, and best results were obtained with the 266 nm laser. The optimized protocol allows the determination of elements down to the sub-mg/kg level with a good accuracy level.

A Non-Matrix-Matched Calibration Method for In Situ Major and Trace Element Analysis of Scheelite by Nanosecond LA-ICP-MS.

In this work, a reliable and robust in situ non-matrix-matched calibration method is proposed for element composition determination in scheelite samples. With external calibration against the silicate glass standard reference material NIST SRM 610, the concentrations of both major elements (Ca and W) and trace elements (Si, Fe, Mo, Y, rare earth elements, etc.) in scheelite are determined using an ArF 193 nm excimer nanosecond laser ablation-inductively coupled plasma mass spectrometer (LA-ICP-MS). Here, the ablation was performed by hole drilling under a helium (He) environment using a laser spot size of 35 µm and a laser repetition of 5 Hz, and the aerosols were then transported to a quadrupole ICP-MS by a mixture of He and make-up gas argon (Ar) with a total gas flow rate of 1.6 L/min. Results showed that there was no apparent matrix effect between the NIST SRM 610 and scheelite by this proposed method. With internal standardization against W, the obtained concentrations of CaO and WO3 were found to yield an average matrix CaO/WO3 mass fraction ratio of 0.245 (2σ = 0.003, n = 19), which agreed well with the value of 0.243 (2σ = 0.002, n = 15) from electron probe microanalysis (EPMA). Furthermore, the accuracy of trace element analyses with this proposed non-matrix-matched calibration in situ method was evaluated by comparing the concentration results with those from bulk analysis by solution nebulizer ICP-MS (SN-ICP-MS). It was found that the quantification results from LA-ICP-MS and SN-ICP-MS were comparable, in particular showing a relative concentration bias of the total ∑REE+Y contents of less than 2%. This confirmed that scheelites can be accurately analyzed in situ by LA-ICP-MS without matrix-matched calibration standards. By using this developed in situ method, the element compositions in a series of scheelite samples from different W-associated deposits in China were successfully quantified, promising further genetic process investigation and associated geologic activities of the polymetallic resources.

LA-ICP-MS bioimaging demonstrated disturbance of metal ions in the brain of Parkinson's disease model mouse undergoing manganese-enhanced MRI.

Manganese-enhanced MRI (MEMRI) is a powerful tool to study neuronal activity and microarchitecture in vivo. Yet the influence of exogenous manganese on the brain of the Parkinson's disease (PD) model mouse is poorly understood. Laser ablation connected to inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging for tissue section is an ideal tool to simultaneously analyze the metabolism of endogenous metal ions. In this study, DJ-1 knockout PD model mice were subjected to an MnCl2 saline treatment and the distribution of Mn and several other endogenous metal ions in brain regions was assessed by MEMRI and LA-ICP-MS imaging. The results demonstrated that Mn mainly deposited in subcortical regions, such as ventricles, hippocampus (HC), medial preoptic nucleus (MPO), lateral septal nucleus (LS), and ventromedial hypothalamic nucleus (VMH). The enhanced signal-to-noise ratio (S/N) determined by MEMRI for Mn is closely related to the signal in LA-ICP-MS imaging. Significantly, the treatment of MnCl2 disturbs the homeostasis of iron, zinc, copper, and calcium in the DJ-1 mouse, which could result in more severe symptoms of PD. Therefore, the application of MEMRI in the study of neurological disease must be made with caution.

Quantitative mapping of mercury and selenium in mushroom fruit bodies with laser ablation-inductively coupled plasma-mass spectrometry.

This work describes the development of a novel method for quantitative mapping of Hg and Se in mushroom fruit body tissues with laser ablation coupled to inductively coupled plasma-mass spectrometry (LA-ICP-MS). Different parameters of the protocol for preparation of the standards used for quantification via external calibration were assessed, e.g., the dissolution temperature of gelatin standards and the addition of chitosan and L-cysteine as additives to the gelatin-based calibration droplets to better match the sample matrix. While chitosan was not suited for this purpose, the presence of L-cysteine considerably improved the figures of merit of the calibration, leading to limits of detection of 0.006 and 0.3 µg g-1 for Hg and Se, respectively, at a pixel size of 20 × 20 µm. Further, an in-house reference material, ideally suited for the validation of the method for application to mushroom samples, was successfully prepared from a paste of Boletus edulis. The newly developed method was used to investigate the distribution of Hg and Se in tissue sections of five porcini mushroom individuals of three different species (Boletus edulis, Boletus aereus, and Boletus pinophilus) and one sample of a parasol mushroom (Macrolepiota procera). For one sample, additional areas were ablated at higher spatial resolution, with a laser spot size down to 5 µm, which allows a detailed investigation of the spatial distribution of Hg and Se in mushrooms.

Facets of ICP-MS and their potential in the medical sciences-Part 1: fundamentals, stand-alone and hyphenated techniques.

Since its inception in the early 80s, inductively coupled plasma-mass spectrometry has developed to the method of choice for the analysis of elements in complex biological systems. High sensitivity paired with isotopic selectivity and a vast dynamic range endorsed ICP-MS for the inquiry of metals in the context of biomedical questions. In a stand-alone configuration, it has optimal qualities for the biomonitoring of major, trace and toxicologically relevant elements and may further be employed for the characterisation of disrupted metabolic pathways in the context of diverse pathologies. The on-line coupling to laser ablation (LA) and chromatography expanded the scope and application range of ICP-MS and set benchmarks for accurate and quantitative speciation analysis and element bioimaging. Furthermore, isotopic analysis provided new avenues to reveal an altered metabolism, for the application of tracers and for calibration approaches. In the last two decades, the scope of ICP-MS was further expanded and inspired by the introduction of new instrumentation and methodologies including novel and improved hardware as well as immunochemical methods. These additions caused a paradigm shift for the biomedical application of ICP-MS and its impact in the medical sciences and enabled the analysis of individual cells, their microenvironment, nanomaterials considered for medical applications, analysis of biomolecules and the design of novel bioassays. These new facets are gradually recognised in the medical communities and several clinical trials are underway. Altogether, ICP-MS emerged as an extremely versatile technique with a vast potential to provide novel insights and complementary perspectives and to push the limits in the medical disciplines. This review will introduce the different facets of ICP-MS and will be divided into two parts. The first part will cover instrumental basics, technological advances, and fundamental considerations as well as traditional and current applications of ICP-MS and its hyphenated techniques in the context of biomonitoring, bioimaging and elemental speciation. The second part will build on this fundament and describe more recent directions with an emphasis on nanomedicine, immunochemistry, mass cytometry and novel bioassays.

Revisiting the Happy Jack Uraninite Reference Material: A Combined Electron Beam and Laser Ablation In Situ Study.

This new comprehensive in situ mineral-chemical characterisation of the Happy Jack uraninite has discovered additional information regarding matrix effects and trace element homogeneity, relevant to proposals that it could serve as a reference material (RM). On the LA-ICP-MS instrumentation used, there was an absence of discernible matrix effects relative to the silicate glass NIST SRM 610. Lanthanides and Y are found to be very homogeneously distributed in Happy Jack uraninite, Zr, Nb and Ti mass fractions reproducible but only within individual fragments, and other elements still generally heterogeneous. This means that the Happy Jack uraninite can serve as a secondary RM for quality control in studies of natural uraninites. In terms of absolute accuracy and intermediate measurement precision, the Happy Jack uraninite can be used for the homogeneous elements. For elements that are homogeneous within individual fragments only, intermediate measurement precision can still be evaluated, while information values will be obtained for the generally heterogeneous elements. Two distinct groups (high vs. low Zr) were distinguished to exist among different Happy Jack fragments in association with minor variation of REE mass fractions, which possibly explains the observed (heavy) REE discrepancy between in situ laser ablation and bulk solution ICP-MS analyses.

Topical delivery of PD-1 inhibitors with laser-assisted passive diffusion and active intradermal injection: Investigation of cutaneous pharmacokinetics and biodistribution patterns.

BACKGROUND AND OBJECTIVES: Current cancer immunotherapeutic treatment with PD-1 inhibitors is administered systemically. However, a local treatment strategy may be advantageous as it could provide targeted drug delivery as well as attenuate side effects seen with systemic treatments. For keratinocyte cancers, where surgical excision is not always applicable, an alternate local treatment approach would be beneficial. This study aims to examine cutaneous pharmacokinetics and biodistribution of the PD-1 inhibitor nivolumab, locally delivered either by ablative fractional laser (AFL)-assisted passive diffusion or active intradermal injection, in vivo. MATERIALS AND METHODS: In vivo pig skin was either exposed to CO2 AFL (80 mJ/mb by two stacked pulses of 40 mJ/mb) at 5% or 15% density followed by topical application of nivolumab (1 mg/ml, 100 µl/10 × 10 mm) or intradermally injected with nivolumab (1 mg/ml, 100 µl). Cutaneous nivolumab delivery was evaluated at different timepoints (0, 1, 2, 4 hours and 2 days) at two tissue depths (100-800 and 900-1600 µm) by ELISA. Visualization of cutaneous biodistribution was shown in vertical tissue sections using HiLyte FluorTM 488 SE labeled nivolumab for fluorescence microscopy whereas nivolumab was DOTA-tagged with Dysprosium before the laser ablation-inductively coupled plasma-mass spectrometry analysis (LA-ICP-MS). RESULTS: Our in vivo study revealed different pharmacokinetic and biodistribution patterns for the AFL- and injection techniques. A superficial horizontal band-like uptake of nivolumab was provided with AFL-assisted passive diffusion whereas a deep focal deposition was seen with active intradermal injection, compared with controls showing remnant deposition on the skin surface. AFL-assisted nivolumab uptake in upper dermis peaked after 4 hours (p < 0.01). The cutaneous concentration of nivolumab achieved by intradermal injection was markedly higher than with AFL, the highest deposition with intradermal injection was detected at time 0 hours in both upper and deep dermis (p < 0.01) and decreased throughout the study period, although the concentration remained higher compared with saline control injections at all time points (0 hours -2 d) (p < 0.01). CONCLUSION: Local cutaneous delivery of nivolumab with either AFL or intradermal injection revealed two different pharmacokinetic and biodistribution patterns. Passive AFL-assisted diffusion of nivolumab resulted in enhanced uptake after 4 hours, while intradermal actively injected nivolumab showed immediate enhanced cutaneous deposition with retention up to 2 days after injection. The two local delivery techniques show potential for development of individualized treatment strategies depending on the clinical tumor appearance.

Review about Powerful Combinations of Advanced and Hyphenated Sample Introduction Techniques with Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) for Elucidating Trace Element Species in Pathologic Conditions on a Molecular Level.

Element analysis in clinical or biological samples is important due to the essential role in clinical diagnostics, drug development, and drug-effect monitoring. Particularly, the specific forms of element binding, actual redox state, or their spatial distribution in tissue or in single cells are of interest in medical research. This review summarized exciting combinations of sophisticated sample delivery systems hyphenated to inductively coupled plasma-mass spectrometry (ICP-MS), enabling a broadening of information beyond the well-established outstanding detection capability. Deeper insights into pathological disease processes or intracellular distribution of active substances were provided, enabling a better understanding of biological processes and their dynamics. Examples were presented from spatial elemental mapping in tissue, cells, or spheroids, also considering elemental tagging. The use of natural or artificial tags for drug monitoring was shown. In the context of oxidative stress and ferroptosis iron, redox speciation gained importance. Quantification methods for Fe2+, Fe3+, and ferritin-bound iron were introduced. In Wilson's disease, free and exchangeable copper play decisive roles; the respective paragraph provided information about hyphenated Cu speciation techniques, which provide their fast and reliable quantification. Finally, single cell ICP-MS provides highly valuable information on cell-to-cell variance, insights into uptake of metal-containing drugs, and their accumulation and release on the single-cell level.