Laboratory study of spectral induced polarization responses of magnetite - Fe2+ redox reactions in porous media

Spectral Induced Polarization (SIP) phase anomalies in field surveys at contaminated sites have previously been shown to correlate with the occurrence of chemically reducing conditions and/or semiconductive minerals, but the reasons for this are not fully understood. We report a systematic laboratory investigation of the role of the semiconductive mineral magnetite and its interaction with redoxactive versus redox-inactive ions in producing such phase anomalies. The SIP responses of quartz sand with 5% magnetite in solutions containing redox-inactive Ca2+, and Ni2+, versus redox-active Fe2+ were measured across the pH ranges corresponding to adsorption of these metals to magnetite. With redox inactive ions Ca2+ and Ni2+, SIP phase response showed no changes across the pH range 4 to10, corresponding to their adsorption, showing ~30 mrad anomalies peaking at ~59 to 74 Hz. These large phase anomalies are probably caused by polarization of the magnetite-solution interfaces. With the redox-active ion Fe2+, frequency of peak phase res onse decreased progressively from ~46 to ~3 Hz as effluent pH increased from 4 to 7, corresponding to progressive adsorption of Fe2+ to the magnetite surface. The latter frequency (3 Hz) corresponds approximately with those of phase anomalies detected in field surveys reported elsewhere. We conclude that pH sensitivity arises from redox reactions between Fe2+ and magnetite surfaces, with transfer of electrical charge through the bulk mineral, as reported in other laboratory investigations. Our results confirm that SIP measurements are sensitive to redox reactions involving charge transfers between adsorbed ions and semiconductive minerals. Phase anomalies seen in field surveys of groundwater contamination and biostimulation may therefore be indicative of iron-reducing conditions, when semiconductive iron minerals such as magnetite are present

Reaction pathways and textural aspects of the replacement of anhydrite by calcite at 25 °C

The replacement of sulfate minerals by calcium carbonate polymorphs (carbonation) has important implications in various geological processes occurring in Earth surface environments. In this paper we report the results of an experimental study of the interaction between anhydrite (100), (010), and (001) surfaces and Na₂CO₃ aqueous solutions under ambient conditions. Carbonation progress was monitored by glancing incidence X-ray diffraction (GIXRD) and scanning electron microscopy (SEM). We show that the reaction progresses through the dissolution of anhydrite and the simultaneous growth of calcite. The growth of calcite occurs oriented on the three anhydrite cleavage surfaces and its formation is accompanied by minor vaterite. The progress of the carbonation always occurs from the outer-ward to the inner-ward surfaces and its rate depends on the anhydrite surface considered, with the (001) surface being much more reactive than the (010) and (100) surfaces. The thickness of the formed carbonate layer grows linearly with time. The original external shape of the anhydrite crystals and their surface details (e.g., cleavage steps) are preserved during the carbonation reaction. Textural characteristics of the transformed regions, such as the gradation in the size of calcite crystals, from ~2 μm in the outer region to ~17 μm at the calcite-anhydrite interface, the local preservation of calcite crystalographic orientation with respect to anhydrite and the distribution of the microporosity mainly within the carbonate layer without development of any significant gap at the calcite-anhydrite interface. Finally, we compare these results on anhydrite carbonation with those on gypsum carbonation and can explain the differences on the basis of four parameters: (1) the molar volume change involved in the replacement process in each case, (2) the lack/existence of epitactic growth between parent and product phases, (3) the kinetics of dissolution of the different surfaces, and (4) the chemical composition (amount of structural water) of the parent phases

How Short-Lived Ikaite Affects Calcite Crystallization

The pathways of CaCO₃ crystallization are manifold, often involving one or several metastable amorphous or nanocrystalline intermediate phases. The presence of such intermediates is often overlooked, because they are short-lived and/or occur at small molar fractions. However, their occurrence does not just impact the mechanisms and pathways of formation of the final stable CaCO₃ phase, but also affects their crystal size, shape, and structure. Here we document the presence of a short-lived intermediate through in situ and time-resolved small and wide-angle X-ray scattering combined with high resolution electron microscope observations. When ikaite forms concomitant with the dissolution of amorphous calcium carbonate (ACC) but prior to calcite formation, fairly large glendonite-type calcite crystals grow despite the presence of citrate ligands that usually reduce crystal size. These were ideal seeding crystals for further crystallization from supersaturated ions in solution. In contrast, in the absence of ikaite the crystallization of calcite proceeds through transformation from ACC, resulting in fine-grained spherulitic calcite with sizes ∼8 times smaller than when ikaite was present. Noteworthy is that the formation of the intermediate ikaite, although it consumes less than 3 mol % of the total precipitated CaCO₃, still clearly affected the calcite formation mechanism

Diagnostic amyloid proteomics: experience of the UK National Amyloidosis Centre

Systemic amyloidosis is a serious disease which is caused when normal circulating proteins misfold and aggregate extracellularly as insoluble fibrillary deposits throughout the body. This commonly results in cardiac, renal and neurological damage. The tissue target, progression and outcome of the disease depends on the type of protein forming the fibril deposit, and its correct identification is central to determining therapy. Proteomics is now used routinely in our centre to type amyloid; over the past 7 years we have examined over 2000 clinical samples. Proteomics results are linked directly to our patient database using a simple algorithm to automatically highlight the most likely amyloidogenic protein. Whilst the approach has proved very successful, we have encountered a number of challenges, including poor sample recovery, limited enzymatic digestion, the presence of multiple amyloidogenic proteins and the identification of pathogenic variants. Our proteomics procedures and approaches to resolving difficult issues are outlined

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Impact of inhaled corticosteroids on growth in children with asthma: systematic review and meta-analysis

Background: Long-term inhaled corticosteroids (ICS) may reduce growth velocity and final height of children with asthma. We aimed to evaluate the association between ICS use of >12 months and growth. Methods: We initially searched MEDLINE and EMBASE in July 2013, followed by a PubMed search updated to December 2014. We selected RCTs and controlled observational studies of ICS use in patients with asthma. We conducted random effects meta-analysis of mean differences in growth velocity (cm/year) or final height (cm) between groups. Heterogeneity was assessed using the I2 statistic. Results: We found 23 relevant studies (twenty RCTs and three observational studies) after screening 1882 hits. Meta-analysis of 16 RCTs showed that ICS use significantly reduced growth velocity at one year follow-up (mean difference -0.48 cm/year (95% CI -0.66 to -0.29)). There was evidence of a dose-response effect in three RCTs. Final adult height showed a mean reduction of -1.20 cm (95% CI -1.90 cm to -0.50 cm) with budesonide versus placebo in a high quality RCT. Meta-analysis of two lower quality observational studies revealed uncertainty in the association between ICS use and final adult height, pooled mean difference -0.85 cm (95% CI -3.35 to 1.65). Conclusion: Use of ICS for >12 months in children with asthma has a limited impact on annual growth velocity. In ICS users, there is a slight reduction of about a centimeter in final adult height, which when interpreted in the context of average adult height in England (175 cm for men and 161 cm for women), represents a 0.7% reduction compared to non-ICS users

Biomineralisation by earthworms: an investigation into the stability and distribution of amorphous calcium carbonate

Background Many biominerals form from amorphous calcium carbonate (ACC), but this phase is highly unstable when synthesised in its pure form inorganically. Several species of earthworm secrete calcium carbonate granules which contain highly stable ACC. We analysed the milky fluid from which granules form and solid granules for amino acid (by liquid chromatography) and functional group (by Fourier transform infrared (FTIR) spectroscopy) compositions. Granule elemental composition was determined using inductively coupled plasma-optical emission spectroscopy (ICP-OES) and electron microprobe analysis (EMPA). Mass of ACC present in solid granules was quantified using FTIR and compared to granule elemental and amino acid compositions. Bulk analysis of granules was of powdered bulk material. Spatially resolved analysis was of thin sections of granules using synchrotron-based μ-FTIR and EMPA electron microprobe analysis. Results The milky fluid from which granules form is amino acid-rich (≤ 136 ± 3 nmol mg−1 (n = 3; ± std dev) per individual amino acid); the CaCO3 phase present is ACC. Even four years after production, granules contain ACC. No correlation exists between mass of ACC present and granule elemental composition. Granule amino acid concentrations correlate well with ACC content (r ≥ 0.7, p ≤ 0.05) consistent with a role for amino acids (or the proteins they make up) in ACC stabilisation. Intra-granule variation in ACC (RSD = 16%) and amino acid concentration (RSD = 22–35%) was high for granules produced by the same earthworm. Maps of ACC distribution produced using synchrotron-based μ-FTIR mapping of granule thin sections and the relative intensity of the ν2: ν4 peak ratio, cluster analysis and component regression using ACC and calcite standards showed similar spatial distributions of likely ACC-rich and calcite-rich areas. We could not identify organic peaks in the μ-FTIR spectra and thus could not determine whether ACC-rich domains also had relatively high amino acid concentrations. No correlation exists between ACC distribution and elemental concentrations determined by EMPA. Conclusions ACC present in earthworm CaCO3 granules is highly stable. Our results suggest a role for amino acids (or proteins) in this stability. We see no evidence for stabilisation of ACC by incorporation of inorganic components

All clinically-relevant blood components transmit prion disease following a single blood transfusion: a sheep model of vCJD

Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. Whilst the epidemic appears to be waning, there is much concern that vCJD infection may be perpetuated in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported and linked to blood collected from pre-clinically affected donors. Using an animal model in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components are vectors for prion disease transmission, and highlight the importance of multiple control measures to minimise the risk of human to human transmission of vCJD by blood transfusion

Clinical ApoA-IV amyloid is associated with fibrillogenic signal sequence

Apolipoprotein A-IV amyloidosis is an uncommon form of the disease normally resulting in renal and cardiac dysfunction. ApoA-IV amyloidosis was identified in sixteen patients attending the National Amyloidosis Centre and in eight clinical samples received for histology review. Unexpectedly, proteomics identified the presence of ApoA-IV signal sequence residues (p.18–43 to p.20–43) in 16/24 trypsin-digested amyloid deposits, but in only 1/266 non-ApoA-IV amyloid samples examined. These additional signal residues were also detected in the cardiac sample from the Swedish patient in which ApoA-IV amyloid was first described, and in plasma from a single cardiac ApoA-IV amyloidosis patient. The most common signal-containing peptide observed in ApoA-IV amyloid, p.20–43 and to far lesser extent the N-terminal peptide, p.21–43 were fibrillogenic in vitro at physiological pH generating Congo red positive fibrils. The addition of a single signal-derived alanine residue to the N-terminus has resulted in markedly increased fibrillogenesis. If this effect translates to the mature circulating protein in vivo, then the presence of signal may result in preferential deposition as amyloid, perhaps acting as seed for the main circulating native form of the protein; it may also influence other ApoA-IV associated pathologies