A paleosol record of the evolution of Cr redox cycling and evidence for an increase in atmospheric oxygen during the Neoproterozoic.

Atmospheric oxygen levels control the oxidative side of key biogeochemical cycles and place limits on the development of high-energy metabolisms. Understanding Earth's oxygenation is thus critical to developing a clearer picture of Earth's long-term evolution. However, there is currently vigorous debate about even basic aspects of the timing and pattern of the rise of oxygen. Chemical weathering in the terrestrial environment occurs in contact with the atmosphere, making paleosols potentially ideal archives to track the history of atmospheric O2 levels. Here we present stable chromium isotope data from multiple paleosols that offer snapshots of Earth surface conditions over the last three billion years. The results indicate a secular shift in the oxidative capacity of Earth's surface in the Neoproterozoic and suggest low atmospheric oxygen levels (<1% PAL pO2 ) through the majority of Earth's history. The paleosol record also shows that localized Cr oxidation may have begun as early as the Archean, but efficient, modern-like transport of hexavalent Cr under an O2 -rich atmosphere did not become common until the Neoproterozoic.

Highly fractionated chromium isotopes in Mesoproterozoic-aged shales and atmospheric oxygen.

The history of atmospheric oxygen through the Mesoproterozoic Era is uncertain, but may have played a role in the timing of major evolutionary developments among eukaryotes. Previous work using chromium isotopes in sedimentary rocks has suggested that Mesoproterozoic Era atmospheric oxygen levels were too  low in concentration (<0.1% of present-day levels (PAL)) for the expansion of eukaryotic algae and for the evolution of crown-group animals that occurred later in the Neoproterozoic Era. In contrast, our new results on chromium isotopes from Mesoproterozoic-aged sedimentary rocks from the Shennongjia Group from South China is consistent with atmospheric oxygen concentrations of >1% PAL and thus the possibility that a permissive environment existed long before the expansion of various eukaryotic clades.

Chromium isotope fractionation during Cr(VI) reduction in a methane-based hollow-fiber membrane biofilm reactor.

Chromium (Cr) isotope fractionation analysis is a promising tool for monitoring Cr(VI) reduction in natural aqueous systems. In addition, large amounts of CH4 in natural aqueous sediments are oxidized to CO2 through methanotrophs, thereby mitigating emissions to the atmosphere. However, the investigations on the Cr(VI) reduction process with methanotrophs, and the associated Cr isotope fractionation patterns are scarce. In this study, we have shown that Cr(VI) reduction can occur in the presence of CH4 as the sole electron donor in a hollow-fiber membrane reactor (HfMBR) after direct bacteria enrichment from sediment samples. Products of the methane oxidation by the methanotrophs are used by microbes to reduce Cr(VI) as shown by the progressive increase in δ53Cr with time in the CH4 feed reactor. The isotope fractionation factor (ε) of -2.62 ± 0.20‰ was obtained from the application of the Rayleigh distillation model. The results of Cr isotope fractionation analysis also explained the decrease of Cr(VI) concentration in the N2 feed reactor, where the δ53Cr values remained steady in the first two weeks but significantly increased in the last two weeks, indicating that physical adsorption and subsequent Cr(VI) reduction occurred. This study extended the application of Cr isotope fractionation, showing the suitability of this method for clarifying different Cr(VI) removal processes.

Red blood cell concentrates treated with the amustaline (S-303) pathogen reduction system and stored for 35 days retain post-transfusion viability: results of a two-centre study.

BACKGROUND AND OBJECTIVES: Pathogen reduction technology using amustaline (S-303) was developed to reduce the risk of transfusion-transmitted infection and adverse effects of residual leucocytes. In this study, the viability of red blood cells (RBCs) prepared with a second-generation process and stored for 35 days was evaluated in two different blood centres. MATERIALS AND METHODS: In a single-blind, randomized, controlled, two-period crossover study (n = 42 healthy subjects), amustaline-treated (Test) or Control RBCs were prepared in random sequence and stored for 35 days. On day 35, an aliquot of 51 Cr/99m Tc radiolabeled RBCs was transfused. In a subgroup of 26 evaluable subjects, 24-h RBC post-transfusion recovery, mean life span, median life span (T50 ) and life span area under the curve (AUC) were analysed. RESULTS: The mean 24-h post-transfusion recovery of Test and Control RBCs was comparable (83·2 ± 5·2 and 84·9 ± 5·9%, respectively; P = 0·06) and consistent with the US Food and Drug Administration (FDA) criteria for acceptable RBC viability. There were differences in the T50 between Test and Control RBCs (33·5 and 39·7 days, respectively; P < 0·001), however, these were within published reference ranges of 28-35 days. The AUC (per cent surviving × days) for Test and Control RBCs was similar (22·6 and 23·1 per cent surviving cells × days, respectively; P > 0·05). Following infusion of Test RBCs, there were no clinically relevant abnormal laboratory values or adverse events. CONCLUSION: RBCs prepared using amustaline pathogen reduction meet the FDA criteria for post-transfusion recovery and are metabolically and physiologically appropriate for transfusion following 35 days of storage.

Dual Mechanism Conceptual Model for Cr Isotope Fractionation during Reduction by Zerovalent Iron under Saturated Flow Conditions.

Chromium isotope analysis is rapidly becoming a valuable complementary tool for tracking Cr(VI) treatment in groundwater. Evaluation of various treatment materials has demonstrated that the degree of isotope fractionation is a function of the reaction mechanism, where reduction of Cr(VI) to Cr(III) induces the largest fractionation. However, it has also been observed that uniform flow conditions can contribute complexity to isotope measurements. Here, laboratory batch and column experiments were conducted to assess Cr isotope fractionation during Cr(VI) reduction by zerovalent iron under both static and saturated flow conditions. Isotope measurements were accompanied by traditional aqueous geochemical measurements (pH, Eh, concentrations) and solid-phase analysis by scanning electron microscopy and X-ray absorption spectroscopy. Increasing δ(53)Cr values were associated with decreasing Cr(VI) concentrations, which indicates reduction; solid-phase analysis showed an accumulation of Cr(III) on the iron. Reactive transport modeling implemented a dual mechanism approach to simulate the fractionation observed in the experiments. The faster heterogeneous reaction pathway was associated with minimal fractionation (ε=-0.2‰), while the slower homogeneous pathway exhibited a greater degree of fractionation (ε=-0.9‰ for the batch experiment, and ε=-1.5‰ for the column experiment).

Earth history. Low mid-Proterozoic atmospheric oxygen levels and the delayed rise of animals.

The oxygenation of Earth's surface fundamentally altered global biogeochemical cycles and ultimately paved the way for the rise of metazoans at the end of the Proterozoic. However, current estimates for atmospheric oxygen (O2) levels during the billion years leading up to this time vary widely. On the basis of chromium (Cr) isotope data from a suite of Proterozoic sediments from China, Australia, and North America, interpreted in the context of data from similar depositional environments from Phanerozoic time, we find evidence for inhibited oxidation of Cr at Earth's surface in the mid-Proterozoic (1.8 to 0.8 billion years ago). These data suggest that atmospheric O2 levels were at most 0.1% of present atmospheric levels. Direct evidence for such low O2 concentrations in the Proterozoic helps explain the late emergence and diversification of metazoans.

Construction and evaluation of a novel humanized HER2-specific chimeric receptor.

INTRODUCTION: The human epidermal growth factor receptor 2 (HER2) represents one of the most studied tumor-associated antigens (TAAs) for cancer immunotherapy. The monoclonal antibody (mAb) trastuzumab has improved the outcomes of patients with HER2+ breast cancer. However, a large number of HER2+ tumors are not responsive to, or become resistant to, trastuzumab-based therapy, and thus more effective therapies targeting HER2 are needed. METHODS: HER2-specific T cells were generated by the transfer of genes that encode chimeric antigen receptor (CAR). Using a multistep overlap extension PCR method, we constructed a novel, humanized HER2 CAR-containing, chA21 single-chain variable fragment (scFv) region of antigen-specific mAb and T-cell intracellular signaling chains made up of CD28 and CD3ζ. An interferon γ and interleukin 2 enzyme-linked immunosorbent assay and a chromium-51 release assay were used to evaluate the antitumor immune response of CAR T cells in coculture with tumor cells. Furthermore, SKBR3 tumor-bearing nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice were treated with HER2 CAR T cells to evaluate antitumor activity. Human CD3+ T cell accumulation in tumor xenograft was detected by immunohistochemistry. RESULTS: chA21-28z CAR was successfully constructed, and both CD4+ and CD8+ T cells were transduced. The expanded HER2 CAR T cells expressed a central memory phenotype and specifically reacted against HER2+ tumor cell lines. Furthermore, the SKBR3 tumor xenograft model revealed that HER2 CAR T cells significantly inhibited tumor growth in vivo. Immunohistochemical analysis showed robust accumulation of human CD3+ T cells in regressing SKBR3 lesions. CONCLUSIONS: The results of this study show that novel chA21 scFv-based, HER2-specific CAR T cells not only recognized and killed HER2+ breast and ovarian cancer cells ex vivo but also induced regression of experimental breast cancer in vivo. Our data support further exploration of the HER2 CAR T-cell therapy for HER2-expressing cancers.

Common occurrence of a positive δ53Cr shift in Central European waters contaminated by geogenic/industrial chromium relative to source values.

Carcinogenic effects of hexavalent chromium in waters are of concern in many countries worldwide. We explored Cr isotope systematics at 11 sites in the Czech Republic and Poland. Geogenic Cr pollution was associated with serpentinite bodies at former convergent plate margins, while anthropogenic Cr pollution resulted from electroplating, tanning, and the chemical industry. Cr(VI) concentration in geogenic waters was less than 40 ppb. Anthropogenic waters contained up to 127,000 ppb Cr(VI). At both geogenic and anthropogenic sites, where known, the source of pollution had a low δ53Cr (<1‰). δ53Cr of geogenic and anthropogenic waters was up to 3.9 and 5.8‰, respectively. At both serpentinite-dominated and industrial sites, δ53Cr(VI)aq was shifted toward higher values, compared to the pollution source. At the industrial sites, this positive δ53Cr shift was related to Cr(VI) reduction, a process known to fractionate Cr isotopes. At geogenic sites, the origin of high δ53Cr(VI)aq is tentatively ascribed to preferential release of 53Cr during oxidation of soil Cr(III) and its mobilization to water. δ53Cr(VI) of industrially contaminated waters was significantly higher (p<0.001) compared to δ53Cr of waters carrying geogenic Cr(VI), implying that either the effective fractionation factor or process extent was greater for Cr(VI) reduction than for Cr(III) oxidation.

Cr stable isotopes in Snake River Plain aquifer groundwater: evidence for natural reduction of dissolved Cr(VI).

At Idaho National Laboratory, Cr(VI) concentrations in a groundwater plume once exceeded regulatory limits in some monitoring wells but have generally decreased over time. This study used Cr stable isotope measurements to determine if part of this decrease resulted from removal of Cr(VI) via reduction to insoluble Cr(III). Although waters in the study area contain dissolved oxygen, the basalt host rock contains abundant Fe(II) and may contain reducing microenvironments or aerobic microbes that reduce Cr(VI). In some contaminated locations, (53)Cr/(52)Cr ratios are close to that of the contaminant source, indicating a lack of Cr(VI) reduction. In other locations, ratios are elevated. Part of this shift may be caused by mixing with natural background Cr(VI), which is present at low concentrations but in some locations has elevated (53)Cr/(52)Cr. Some contaminated wells have (53)Cr/(52)Cr ratios greater than the maximum attainable by mixing between the inferred contaminant and the range of natural background observed in several uncontaminated wells, suggesting that Cr(VI) reduction has occurred. Definitive proof of reduction would require additional evidence. Depth profiles of (53)Cr/(52)Cr suggest that reduction occurs immediately below the water table, where basalts are likely least weathered and most reactive, and is weak or nonexistent at greater depth.

Speciated isotope dilution analysis of Cr(III) and Cr(VI) in water by ICP-DRC-MS.

An isotope dilution method has been developed for the speciation analysis of chromium in natural waters which accounts for species interconversions without the requirement of a separation instrument connected to the mass spectrometer. The method involves (i) in-situ spiking of the sample with isotopically enriched chromium species; (ii) separation of chromium species by precipitation with iron hydroxide; (iii) careful measurement of isotope ratios using an inductively coupled plasma mass spectrometer (ICP-MS) with a dynamic reaction cell (DRC) to remove isobaric polyatomic interferences. The method detection limits are 0.4 microg L(-1) for Cr(III) and 0.04 microg L(-1) for Cr(VI). The method is demonstrated for the speciation of Cr(III) and Cr(VI) in local nullah and synthetically spiked water samples. The percentage of conversion from Cr(III) to Cr(VI) increased from 5.9% to 9.3% with increase of the concentration of Cr(VI) and Cr(III) from 1 to 100 microg L(-1), while the reverse conversion from Cr(VI) to Cr(III) was observed within a range between 0.9% and 1.9%. The equilibrium constant for the conversion was found to be independent of the initial concentrations of Cr(III) and Cr(VI) and in the range of 1.0 (at pH 3) to 1.8 (at pH 10). The precision of the method is better than that of the DPC method for Cr(VI) analysis, with the added bonuses of freedom from interferences and simultaneous Cr(III) determination.

Combinations of tumor-specific CD8+ CTLs and anti-CD25 mAb provide improved immunotherapy.

One new approach to cancer therapy is based on the adoptive transfer of tumor-specific cytotoxic T cells and anti-CD25 antibodies. In the present study, CD8+ and IFN-gamma secreting T lymphocytes (CTLs) were enriched as tumor-specific cytotoxic T cells from spleen lymphocytes of mice bearing the Renca tumor (a murine renal carcinoma line originating from a BALB/c mouse) after stimulation with tumor cells. An anti-CD25 IL-2Ralpha(anti-CD25) mAb from hybridoma PC61 was used for depletion for CD4(+)CD25(+) regulatory T (Treg) cells. Treatment-efficacy for tumor-bearing mice was compared using 4 systems: 1, whole spleen lymphocytes stimulated with tumor cells in vitro from tumor-bearing mice; 2, CTLs; 3, anti-CD25 mAbs; 4, CTLs and anti-CD25 mAbs. At the 50th day after tumor inoculation, in the group which received anti-CD25 mAb for depletion of T cells and inoculation of CTLs, tumors had disappeared and no re-growth was observed. In contrast, all mice of the non-treated and other three groups, treated with whole spleen cells alone, CTLs alone and anti-CD25 mAb alone, had died. These results showed that a combination of Treg cell-depletion using anti-CD25 mAbs and CTL administration is a feasible approach for treatment of cancers which warrants further exploration in the clinical setting.

Using chromium stable isotope ratios to quantify Cr(VI) reduction: lack of sorption effects.

Chromium stable isotope values can be effectively used to monitor reduction of Cr(VI) in natural waters. We investigate effects of sorption during transport of Cr(VI) which may also shift Cr isotopes values, complicating efforts to quantify reduction. This study shows that Cr stable isotope fractionation caused by sorption is negligible. Equilibrium fractionation of Cr stable isotopes between dissolved Cr(VI) and Cr(VI) adsorbed onto gamma-Al2O3 and goethite is less than 0.04 per thousand (53Cr/52Cr) under environmentally relevant pH conditions. Batch experiments at pH 4.0 and pH 6.0 were conducted in series to sequentially magnify small isotope fractionations. A simple transport model suggests that adsorption may cause amplification of a small isotope fractionation along extreme fringes of a plume, leading to shifts in 53Cr/52Cr values. We therefore suggest that isotope values at extreme fringes of Cr plumes be critically evaluated for sorption effects. A kinetic effect was observed in experiments with goethite at pH 4 where apparently lighter isotopes diffuse into goethite clumps at a faster rate before eventually reaching equilibrium. This observed kinetic effect may be important in a natural system that has not attained equilibrium and is in need of further study. Cr isotope fractionation caused by speciation of Cr(VI) between HCrO4- and CrO4(2-) was also examined, and we conclude that it is not measurable. In the absence of isotope fractionation caused by equilibrium speciation and sorption, most of the variation in delta53Cr values may be attributed to reduction, and reliable estimates of Cr reduction can be made.

Chromium isotopes and the fate of hexavalent chromium in the environment.

Measurements of chromium (Cr) stable-isotope fractionation in laboratory experiments and natural waters show that lighter isotopes reacted preferentially during Cr(VI) reduction by magnetite and sediments. The 53Cr/52Cr ratio of the product was 3.4 +/- 0.1 per mil less than that of the reactant. 53Cr/52Cr shifts in water samples indicate the extent of reduction, a critical process that renders toxic Cr(VI) in the environment immobile and less toxic.

Removal and recovery of chromium(III) from aqueous solutions by a spheroidal cellulose adsorbent.

The removal and recovery of chromium(III) (Cr3+) from aqueous solutions with a spheroidal cellulose adsorbent containing the carboxyl anionic group was investigated. The adsorption of Cr3+ ion on the adsorbent has been found to be time, concentration, pH, and temperature dependent. The adsorption process follows both the Freundlich and Langmuir adsorption isotherms, and has been found to be endothermic (enthalpy change, deltaH = 31.35 kJ/mol). The Cr3+ ion adsorbed on the adsorbent can be recovered by treating with a sodium hydroxide (NaOH) or hydrochloric acid (HCl) solution in one of two methods, static desorption or mobile desorption (column operation). A 1.2 mol/L HCl aqueous solution was finally chosen to recover the Cr3+ ion using column operation. The recovery percentage is approximately 85.2%. The exhausted column can be chemically regenerated by treatment with 1 mol/L NaOH aqueous solution and no dismantling is required. The adsorption mechanism is explained on the basis of complexation and ion exchange, between which the complexation adsorption is predominant.