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All sourcesNASA NTRSDOE OSTI
DOE OSTI2012

Spectral line intensity irreversibility in circulatory plasma magnetization processes

Spectral line intensity variation is found to be irreversible in circulatory plasma magnetization process by experiments described in this paper, i.e., the curves illustrating spectral line photon fluxes irradiated from a light source immerged in a magnetic field by increasing the magnetic induction cannot be reproduced by decreasing the magnetic induction within the errors. There are two plasma magnetization patterns found. One shows that the intensities are greater at the same magnetic inductions during the magnetic induction decreasing process after the increasing, and the other gives the opposite effect. This reveals that the magneto-induced excitation and de-excitation process is irreversible like ferromagnetic magnetization. But the two irreversible processes are very different in many aspects stated in the text.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2013

Effect of resistivity profile on current decay time of initial phase of current quench in neon-gas-puff inducing disruptions of JT-60U

According to an early work [Y. Shibata et al., Nucl. Fusion 50, 025015 (2010)] on the behavior of the plasma current decay in the JT-60U disruptive discharges caused by the radiative collapse with a massive neon-gas-puff, the increase of the internal inductance mainly determined the current decay time of plasma current during the initial phase of current quench. To investigate what determines the increase of the internal inductance, we focus attention on the relationship between the electron temperature (or the resistivity) profile and the time evolution of the current density profile and carry out numerical calculations. As a result, we find the reason of the increase of the internal inductance: The current density profile at the start of the current quench is broader than an expected current density profile in the steady state, which is determined by the temperature (or resistivity) profile. The current density profile evolves into peaked one and the internal inductance is increasing.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2020

Wind farm blockage effects: comparison of different engineering models

The work presents four engineering methods to estimate the induction zone in front of a wind turbine and account for the wind farm blockage effect. The methods comprise the vortex cylinder model, vortex dipole model, self-similar model, and wake projection model. The majority of the models presented account for yaw misalignments and ground effect. Actuator disk simulations are used to verify the individual models. The performance of each model is evaluated both in terms of precision and computational time. The induction models are coupled to wake models within the FLOw Redirection and Induction in Steady State framework to provide the full velocity field within a wind farm. Sample wind farm computations are presented, and the impact of including induction effects into wind farm performance predictions is reported. The different codes are publicly available online.

17 WIND ENERGY↗
DOE OSTI2012

Variation of Apoptotic Pathway Regulators by Fotemustine and Protons in a Human Melanoma Cell Line

The effects of combined treatments with fotemustine and proton radiation on cell proliferation and induction of apoptosis have been analyzed in this study. HTB140 human melanoma cells were treated with fotemustine (100, 250 M) 24 h prior to irradiation (12, 16 Gy). The cells were irradiated in the middle of a therapeutic 62 MeV proton spread-out Bragg peak. An efficiency of applied treatments was observed throughout the evaluation of the cell proliferation 7 days after proton irradiation. The combined treatments with fotemustine and protons resulted in a greater antiproliferative response than each treatment alone. The number of apoptotic cells was estimated after 6 or 48 h using flow cytometry. The highest percentage of apoptotic cells was obtained 48 h after treatment with 250 M fotemustine and protons. Western blot analysis showed that induction of apoptosis was associated with p53 and Bax up regulation, and Bcl-2 down regulation. The induction of a caspase-3 activity and cleavage of PARP were clearly observed. These data indicate that a combined application of FM and proton irradiation is more effective in reducing melanoma cell proliferation and the induction of apoptosis, suggesting that FM can increase the radio-sensitivity of HTB140 melanoma cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Concentration of HLLW from Future SNF Recycling for Efficient Immobilization in a CCIM

Sponsored by the Department of Energy Nuclear Energy’s Fuel Cycle Research and Development Program, the Cold Crucible Induction Melter is being developed as the next generation of melter technology for High Level Liquid Waste’s efficient immobilization in highly durable glass ceramic and ceramic forms. Concentration of the radioactive High Level Liquid Waste generated from the proposed future recycling of spent nuclear fuel, after the fuel’s dissolution in nitric acid, is necessary to take advantage of the inherent attributes of Cold Crucible Induction Melting technology. Based on a provided range of commercial spent nuclear fuel fission product composition data and its expected High Level Liquid Waste raffinate composition data as provided in oxide form, an analysis was completed to concentrate the waste. The analysis involved using nitric acid vapor liquid equilibrium data over a range of boiling temperatures and performing spreadsheet calculations to concentrate the High Level Liquid Waste through evaporation. The calculation results will provide a concentrated nonradioactive surrogate High Level Liquid Waste melter feed recipe for testing in Idaho National Laboratory’s Cold Crucible Induction Melter Pilot Plant. This testing will provide a quantifiable verification of the relatively high feed rates of Cold Crucible Induction Melters compared to those achievable with the current ceramic lined Joule Heated Melters.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2018

CHI Research. Final Technical Report

The spherical tokamak is a leading candidate for a Fusion Nuclear Science Facility (FNSF) due to its compact size and modular configuration. It is highly desirable for the FNSF to be compact in size and simpler in configuration. Since the central solenoid cannot be used for driving current during the steady-state phase, the tokamak design would also be simplified if it could be built without the solenoid, and it would allow access to lower aspect ratio configurations. Great progress has been made in developing Transient CHI as a viable solenoid-free plasma start-up method. These are: (a) The generation of closed flux current in HIT-II and NSTX, and the successful coupling of this current to induction from the central solenoid, (b) the generation of 0.1 MA closed flux current in HIT-II and demonstration of CHI plasma quality similar to that produced inductively, (c) the generation of a record 0.2 MA of closed flux current in NSTX and the coupling of the CHI-produced discharge in NSTX to induction with subsequent transitioning to a high-performance H-mode discharge when neutral beams were injected and (e) CHI-started discharges to which induction has been applied have ramped-up to 1 MA in NSTX with record low flux consumption. Modeling of the CHI process using TSC and NIMROD has led to a much-improved understanding of the physics of magnetic reconnection leading to large volume flux closure. The NIMROD results indicate that this reconnection mechanism scales to arbitrarily high toroidal field and can be either axisymmetric Sweet-Parker like reconnection or it can be enhanced through plasmoid formation. Motivated by the exciting experimental and modeling results from HIT-II and NSTX, we explored the application of CHI to a reactor configuration, and identified methods for enabling CHI capability in a FNSF-sized experiment. In the first, proven, concept referred to as "NSTX-like", the entire blanket structure is insulated from the vessel using insulating supports. In the second configuration referred to as "DIII-D - like", a toroidal insulated electrode is placed on top of the blanket structure to shield the insulator from neutrons, allowing more than six years of full power operations before insulator replacement. The second concept requires an experimental test for concept validation. To test this second concept, during the period of 2013 to 2016, we designed and implemented a new simpler design CHI configuration on QUEST. Initial TSC modeling and experimental results suggests that work on QUEST may lead to a simpler Transient CHI configuration for a ST-FNSF. Transient CHI is now also in the process of being implemented on the PEGASUS ST at the University of Washington to study very high-current start-up potential of transient CHI.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
NASA NTRS2001

Evolution of the organizer and the chordate body plan

The discovery of the organizer by Spemann and Mangold in 1924 raised two kinds of questions: those about the means of patterning the chordate body axis and those about the mechanisms of cell determination by induction. Some researchers, stressing the second, have suggested over the years that the organizer is poorly named and doesn't really organize because inducers act permissively, because they are not unique to the organizer, and because multipotent responsive cells develop complex local differentiations under artificial conditions. Furthermore, with the discovery of meso-endoderm induction in 1969, the possibility arose that this earlier induction generates as much organization as, or more than, does the organizer itself. Evidence is summarized in this article that the organizer does fulfill its title with regard to pattern formation: it adds greatly to embryonic organization by providing information about time, place, scale, and orientation for development by nearby members of the large multipotent competence groups surrounding the organizer. Embryos having smaller or larger organizers due to experimental intervention develop defective axial organization. Without an organizer the embryo develops no body axis and none of the four chordate characters: the notochord, gill slits, dorsal hollow nerve chord, and post-anal tail. For normal axis formation, the organizer's tripartite organization is needed. Each part differs in inducers, morphogenesis, and self-differentiation. The organizer is a trait of development of all members of the chordate phylum. In comparison to hemichordates, which constitute a phylum with some similarities to chordates, the chordamesoderm part is unique to the chordate organizer (the trunk-tail organizer). Its convergent extension displaces the gastrula posterior pole from alignment with the animal-vegetal axis and generates a new anteroposterior axis orthogonal to this old one. Once it has extended to full length, its signaling modifies the dorsoventral dimension. This addition to the organizer is seen as a major event in chordate evolution, bringing body organization beyond that achieved by oocyte organization and meso-endoderm induction in other groups.

Non-NASA Center↗
DOE OSTI2018

Vitrification of High-Level Waste: how to Select the Best Suited Technology - 18117

Since more than 30 years now, a number of countries have selected and operated vitrification as the best industrial practice for safely and durably immobilizing the most active liquid waste. This now significant worldwide experience covers a wide range of waste compositions, from concentrated alkaline defense waste sludges with a variety of salts and chemicals (Na, Fe, Al, Cr, sulphate,... ) to relatively clear acidic HLLW from commercial, low salt, PUREX-type processes, waste that include dissolved cladding material (Al, Mg, stainless steel), waste that include high levels of noble metals and fines... The activity levels vary from 40- year old defense waste to relatively young waste from high burn-up commercial fuel. The current throughputs vary from about 5 kg/h of glass to about 90 kg/h of glass per melter. Even higher throughputs are currently being considered for Hanford facility for instance. In order to cope with the range of waste compositions, glass compositions have also evolved from low melting temperature borosilicate or phosphate glass to glass or glass ceramics with higher melting temperatures. More complex matrices are currently under study in a number of countries, to immobilize more complex waste and / or increase waste loadings. Each challenge is unique and, for each challenge, it is necessary to select the best combination of waste form and technology. For instance for very active solutions with high levels of noble metal particles that could settle, increase apparent glass viscosity, and impact electrical conductivity, one would select borosilicate glass in the mechanically-stirred hot wall induction melter with bottom pouring that has proven its efficiency in industrial conditions at La Hague. For high glass throughputs with low solids in a borosilicate melt (typically Defense waste), ceramic melters have proven their reliability and efficiency. For matrices that need higher temperatures, or with very high corrosiveness, Cold-Crucible Induction Melters are now considered, with one first industrial implementation at La Hague to produce borosilicate glass and a glass-ceramic. All these technologies have been improved over the years to increase throughput, waste loading, melting temperature, reliability... Other types of waste are now being studied worldwide, and for each, it is necessary to carefully select the adapted waste form and technology. The technologies studied will range from traditional technologies (such as hot-wall induction melter technology and liquid-fed ceramic melter technologies) to the more recent advanced technologies (such as Cold Crucible Induction Melter or Advanced Ceramic melters). In addition, the field of vitrification is extending to other types of waste; the current advances in this field will also be described. (authors)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
DOE OSTI2018

Design and Assembly of SPT-3G Cold Readout Hardware

The third-generation upgrade to the receiver on the South Pole Telescope, SPT-3G, was installed at the South Pole during the 2016–2017 austral summer to measure the polarization of the cosmic microwave background. Increasing the number of detectors by a factor of 10 to ~16,000 required the multiplexing factor to increase to 68 and the bandwidth of the frequency-division readout electronics to span 1.6–5.2 MHz. This increase necessitates low-thermal conductance, low-inductance cryogenic wiring. Our cold readout system consists of planar thin-film aluminum inductive–capacitive resonators, wired in series with the detectors, summed together, and connected to 4K SQUIDs by 10-μm -thick niobium–titanium (NbTi) broadside-coupled striplines. Here, we present an overview of the cold readout electronics for SPT-3G, including assembly details and characterization of electrical and thermal properties of the system. We report, for the NbTi striplines, values of R≤10 -4 Ω , L=21±1 nH , and C=1.47±.02 nF . Additionally, the striplines’ thermal conductivity is described by kA=6.0±0.3 T 0.92±0.04 μW mm K -1 . Finally, we provide projections for cross talk induced by parasitic impedances from the stripline and find that the median value of percentage cross talk from leakage current is 0.22 and 0.09% from wiring impedance.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2019

Microstructure and Properties of Mn-Cu-Based Damping Alloys Prepared by Ball Milling and Hot-Press Sintering

A Mn-Cu-based damping alloy with a nominal composition of 70Mn-24Cu-3Zn-3Al (at.%) was prepared by ball milling of pure elemental powders and subsequent hot-press sintering of powder mixture at 750 and 825 °C for 2 h. For comparison, this alloy was also prepared by induction melting technology and then homogenized at 850 °C for 24 h. Further, they were aged at 430 °C for 2 h. The microstructure, damping capacity and microhardness of the hot-press-sintered and induction-melted alloys have been investigated. The results show that the microstructure of the powder mixture upon ball milling mainly comprises convoluted composite particles containing α-Mn and γ-Cu phases, and isolated α-Mn ones around. The high compactness of the alloys is obtained after hot-press sintering (94.8 and 98.6% at 750 and 825 °C, respectively). At a holding temperature of 750 °C, the microstructure of the alloy is primarily composed of γ-MnCu, γ-CuMn and α-Mn grains. With increasing the target temperature to 825 °C, the single γ-MnCu solid solution has been formed in the alloy by diffusion of Mn etc. into γ-Cu lattices. The hot-press-sintered alloys (especially at 825 °C) possess relatively high damping capacity although which is still lower than that of induction-melted one. In contrast, the microhardness of the hot-press-sintered alloys (especially at 750 °C) is obviously higher than that of the induction-melted one.

36 MATERIALS SCIENCE↗
DOE OSTI2016

Identification of PM{sub 10} characteristics involved in cellular responses in human bronchial epithelial cells (Beas-2B)

Notwithstanding evidence is present that physicochemical characteristics of ambient particles attribute to adverse health effects, there is still some lack of understanding in this complex relationship. At this moment it is not clear which properties (such as particle size, chemical composition) or sources of the particles are most relevant for health effects. This study investigates the in vitro toxicity of PM{sub 10} in relation to PM chemical composition, black carbon (BC), endotoxin content and oxidative potential (OP). In 2013–2014 PM{sub 10} was sampled (24 h sampling, 108 sampling days) in ambient air at three sites in Flanders (Belgium) with different pollution characteristics: an urban traffic site (Borgerhout), an industrial area (Zelzate) and a rural background location (Houtem). To characterize the toxic potential of PM{sub 10}, airway epithelial cells (Beas-2B cells) have been exposed to particles in vitro. Different endpoints were studied including cell damage and death (cell viability) using the Neutral red Uptake assay, the production of pro-inflammatory molecules by interleukin 8 (IL-8) induction and DNA-damaging activity using the FPG-modified Comet assay. The endotoxin levels in the collected samples were analysed and the capacity of PM{sub 10} particles to produce reactive oxygen species (OP) was evaluated by electron paramagnetic resonance (EPR) spectroscopy. Chemical characteristics of PM{sub 10} (BC, As, Cd, Cr, Cu, Mn, Ni, Pb, Zn) and meteorological conditions were recorded on the sampling days. PM{sub 10} particles exhibited dose-dependent cytotoxicity in Beas-2B cells and were found to significantly induce the release of IL-8 in samples from the three locations. Oxidatively damaged DNA was observed in exposed Beas-2B cells. Endotoxin levels above the detection limit were detected in half of the samples. OP was measurable in all samples. Associations between PM{sub 10} characteristics and biological effects of PM{sub 10} were assessed by single and multiple regression analyses. The reduction in cell viability was significantly correlated with BC, Cd and Pb. The induction of IL-8 in Beas-2B cells was significantly associated with Cu, Ni and Zn and endotoxin. Endotoxin levels explained 33% of the variance in IL-8 induction. A significant interaction between ambient temperature and endotoxin on the pro-inflammatory activity was seen. No association was found between OP and the cellular responses. This study supports the hypothesis that, on an equal mass basis, PM{sub 10} induced biological effects differ due to differences in PM{sub 10} characteristics. Metals (Cd, Cu, Ni and Zn), BC, and endotoxin were among the main determinants for the observed biological responses. - Highlights: • On an equal mass basis, PM{sub 10} sampled at an urban, rural and industrial site induced different cellular effects in Beas-2B. • Endotoxin levels and oxidative potential (OP) were analysed in the PM{sub 10} samples. • Black carbon, cadmium and lead were correlated with decreased cell viability. • Endotoxin levels explained the majority of the variance in il-8 induction. • Oxidatively damaged DNA was observed in all the samples.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2012

Dosimetric Advantage of Intensity-Modulated Radiotherapy for Whole Ventricles in the Treatment of Localized Intracranial Germinoma

Purpose: To investigate the dosimetric advantage of intensity-modulated radiotherapy (IMRT) for whole ventricles (WV) in patients with a localized intracranial germinoma receiving induction chemotherapy. Methods and Materials: Data from 12 consecutive patients with localized intracranial germinomas who received induction chemotherapy and radiotherapy were used. Four-field coplanar three-dimensional conformal radiotherapy (3D-CRT) and seven-field coplanar IMRT plans were created. In both plans, 24 Gy was prescribed in 12 fractions for the planning target volume (PTV) involving WV and tumor bed. In IMRT planning, optimization was conducted to reduce the doses to the organs at risk (OARs) as much as possible, keeping the minimum dose equivalent to that of 3D-CRT. The 3D-CRT and IMRT plans were compared in terms of the dose-volume statistics for target coverage and the OARs. Results: IMRT significantly increased the percentage volume of the PTV receiving 24 Gy compared with 3D-CRT (93.5% vs. 84.8%; p = 0.007), while keeping target homogeneity equivalent to 3D-CRT (p = 0.869). The absolute percentage reduction in the irradiated volume of the normal brain receiving 100%, 75%, 50%, and 25% of 24 Gy ranged from 0.7% to 16.0% in IMRT compared with 3D-CRT (p < 0.001). No significant difference was observed in the volume of the normal brain receiving 10% and 5% of 24 Gy between IMRT and 3D-CRT. Conformation number was significantly improved in IMRT (p < 0.001). For other OARs, the mean dose to the cochlea was reduced significantly in IMRT by 22.3% of 24 Gy compared with 3D-CRT (p < 0.001). Conclusions: Compared with 3D-CRT, IMRT for WV improved the target coverage and reduced the irradiated volume of the normal brain in patients with intracranial germinomas receiving induction chemotherapy. IMRT for WV with induction chemotherapy could reduce the late side effects from cranial irradiation without compromising control of the tumor.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Predicting Outcome in Patients with Rhabdomyosarcoma: Role of [{sup 18}F]Fluorodeoxyglucose Positron Emission Tomography

Purpose: To evaluate whether [{sup 18}F]fluorodeoxyglucose positron emission tomography (FDG-PET) response of the primary tumor after induction chemotherapy predicts outcomes in rhabdomyosarcoma (RMS). Methods and Materials: After excluding those with initial tumor resection, 107 patients who underwent FDG-PET after induction chemotherapy at Memorial Sloan Kettering Cancer Center from 2002 to 2013 were reviewed. Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated according to FDG-PET response and maximum standardized uptake value (SUV) at baseline (PET1/SUV1), after induction chemotherapy (PET2/SUV2), and after local therapy (PET3/SUV3). Receiver operator characteristic curves were used to determine the optimal cutoff for dichotomization of SUV1 and SUV2 values. Results: The SUV1 (<9.5 vs ≥9.5) was predictive of PFS (P=.02) and OS (P=.02), but not LC. After 12 weeks (median) of induction chemotherapy, 45 patients had negative PET2 scans and 62 had positive scans: 3-year PFS was 72% versus 44%, respectively (P=.01). The SUV2 (<1.5 vs ≥1.5) was similarly predictive of PFS (P=.005) and was associated with LC (P=.02) and OS (P=.03). A positive PET3 scan was predictive of worse PFS (P=.0009), LC (P=.05), and OS (P=.03). Conclusions: [{sup 18}F]fluorodeoxyglucose positron emission tomography is an early indicator of outcomes in patients with RMS. Future prospective trials may incorporate FDG-PET response data for risk-adapted therapy and early assessment of new treatment regimens.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Ultra-thin on-chip ALD LiPON capacitors for high frequency application

Multi-layer ceramic capacitors have been used for high frequency decoupling application due to a lower overall impedance leading to fast current response. However, high parasitic inductance limits the application of these capacitors in ultra-high frequency domain. Thus, Multlayer Ceramic Capacitors (MLCCs) are placed close to the IC to improve circuit efficiency and reduce inductance. With next generation applications, the demand for frequency range has further increased which not only requires enhanced capacitor material but improved manufacturing techniques to limit the inductive path. Here, we demonstrate ALD of two different polymorphs of ultra-thin film lithium phosphorus oxynitride (LiPON) as an inorganic solid state electrolyte (SSE) for on chip capacitors for decoupling application. Both the LiPON capacitors shows an electric double layer behavior with a capacitance of 15 μF/cm 2 and a low leakage current (<20 nA/cm 2 ) at 2V. The LiPON shows EDLC behavior up to 10 kHz and beyond, both the polymorphs show an electrostatic behavior with a high dielectric constant (14). Furthermore, this dual frequency behavior along with low parasitic inductance and on chip integration allows for operation in extended frequency ranges.

25 ENERGY STORAGE↗
DOE OSTI2011

Cardiac toxicity of 5-ring polycyclic aromatic hydrocarbons is differentially dependent on the aryl hydrocarbon receptor 2 isoform during zebrafish development

Petroleum-derived compounds, including polycyclic aromatic hydrocarbons (PAHs), commonly occur as complex mixtures in the environment. Recent studies using the zebrafish experimental model have shown that PAHs are toxic to the embryonic cardiovascular system, and that the severity and nature of this developmental cardiotoxicity varies by individual PAH. In the present study we characterize the toxicity of the relatively higher molecular weight 5-ring PAHs benzo[a]pyrene (BaP), benzo[e]pyrene (BeP), and benzo[k]fluoranthene (BkF). While all three compounds target the cardiovascular system, the underlying role of the ligand-activated aryl hydrocarbon receptor (AHR2) and the tissue-specific induction of the cytochrome p450 metabolic pathway (CYP1A) were distinct for each. BaP exposure (40 {mu}M) produced AHR2-dependent bradycardia, pericardial edema, and myocardial CYP1A immunofluorescence. By contrast, BkF exposure (4-40 {mu}M) caused more severe pericardial edema, looping defects, and erythrocyte regurgitation through the atrioventricular valve that were AHR2-independent (i.e., absent myocardial or endocardial CYP1A induction). Lastly, exposure to BeP (40 {mu}M) yielded a low level of CYP1A+ signal in the vascular endothelium of the head and trunk, without evident toxic effects on cardiac function or morphogenesis. Combined with earlier work on 3- and 4-ring PAHs, our findings provide a more complete picture of how individual PAHs may drive the cardiotoxicity of mixtures in which they predominate. This will improve toxic injury assessments and risk assessments for wild fish populations that spawn in habitats altered by overlapping petroleum-related human impacts such as oil spills, urban stormwater runoff, or sediments contaminated by legacy industrial activities. -- Highlights: Black-Right-Pointing-Pointer PAH compounds with 5 rings in different arrangements caused differential tissue-specific patterns of CYP1A induction in zebrafish embryos. Black-Right-Pointing-Pointer These compounds produced differential cardiac developmental toxicity that did not strictly correlate with associated CYP1A induction. Black-Right-Pointing-Pointer Cardiotoxicity of benzo(a)pyrene was partially dependent on the AHR2 isoform, while benzo(k)fluoranthene cardiotoxicity was not. Black-Right-Pointing-Pointer Individual PAH compounds have distinct toxicokinetic pathways in fish embryos, and act through different toxic mechanisms.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Monitoring Cyp2b10 mRNA expression at cessation of 2-year carcinogenesis bioassay in mouse liver provides evidence for a carcinogenic mechanism devoid of human relevance: The dalcetrapib experience

Introduction: Dalcetrapib is a cholesteryl ester transfer protein (CETP) modulator in clinical assessment for cardiovascular outcome benefits. In compliance with regulatory requirements, dalcetrapib was evaluated in rodent 2-year carcinogenesis bioassays. In the mouse bioassay, male mice demonstrated increased liver weight and statistically increased incidences of hepatocellular adenoma/carcinoma. Hepatic cytochrome p450 (Cyp) 2b10 mRNA induction and increased Cyp2b10 enzyme activity signify activation of hepatic nuclear receptor constitutive androstane receptor (CAR), a widely established promoter of rodent-specific hepatic tumors. We therefore monitored hepatic Cyp2b10 mRNA and its enzyme activity in a subset of dalcetrapib-treated male mice from the bioassay. Methods: Liver samples were obtained from ∼ 1/3 of male mice from each dose group including vehicle-controls (mean and earliest study day of death 678 and 459 respectively). Quantitative real time PCR (qRT-PCR) was performed to determine Cyp2b10 mRNA expression and Cyp1a-, Cyp2b10- and Cyp3a-selective activities were monitored. Results: Cyp2b10 mRNA was strongly induced by dalcetrapib with an expected wide inter-individual variation (5–1421-fold). Group average fold-induction versus vehicle-controls showed a dose-related increase from 48-fold (250 mg/kg/day) to 160-fold (750 mg/kg/day), which declined slightly at 2000 mg/kg/day (97-fold). Cyp enzyme activities showed approximate doubling of total Cyp P450 content per milligram protein and a 9-fold increase in Cyp2b10-selective pentoxyresorufin O-dealkylase activity (750 mg/kg/day). Discussion: These data from hepatic Cyp2b10 monitoring are strongly suggestive of CAR activation by dalcetrapib, a mechanism devoid of relevance towards hepatocarcinogenesis in humans; results show feasibility of Cyp2b10 as a surrogate marker for this mechanism at cessation of a carcinogenesis bioassay. -- Highlights: ► Liver tumors were induced in male mice by dalcetrapib in a 2-y study (bioassay). ► Cyp2b10 induction typifies activation of nuclear receptor CAR in mouse liver. ► First report of hepatic Cyp2b10 monitoring at the end of a mouse bioassay. ► Cyp2b10 induction supports CAR activation by dalcetrapib in mouse bioassay. ► CAR activation is a mechanism of hepatic tumorigenesis of no relevance to humans.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Relative contribution of CTR1 and DMT1 in copper transport by the blood–CSF barrier: Implication in manganese-induced neurotoxicity

The homeostasis of copper (Cu) in the cerebrospinal fluid (CSF) is partially regulated by the Cu transporter-1 (CTR1) and divalent metal transporter-1 (DMT1) at the blood–CSF barrier (BCB) in the choroid plexus. Data from human and animal studies suggest an increased Cu concentration in blood, CSF, and brains following in vivo manganese (Mn) exposure. This study was designed to investigate the relative role of CTR1 and DMT1 in Cu transport under normal or Mn-exposed conditions using an immortalized choroidal Z310 cell line. Mn exposure in vitro resulted in an increased cellular {sup 64}Cu uptake and the up-regulation of both CTR1 and DMT1. Knocking down CTR1 by siRNA counteracted the Mn-induced increase of {sup 64}Cu uptake, while knocking down DMT1 siRNA resulted in an increased cellular {sup 64}Cu uptake in Mn-exposed cells. To distinguish the roles of CTR1 and DMT1 in Cu transport, the Z310 cell-based tetracycline (Tet)-inducible CTR1 and DMT1 expression cell lines were developed, namely iZCTR1 and iZDMT1 cells, respectively. In iZCTR1 cells, Tet induction led to a robust increase (25 fold) of {sup 64}Cu uptake with the time course corresponding to the increased CTR1. Induction of DMT1 by Tet in iZDMT1 cells, however, resulted in only a slight increase of {sup 64}Cu uptake in contrast to a substantial increase in DMT1 mRNA and protein expression. These data indicate that CTR1, but not DMT1, plays an essential role in transporting Cu by the BCB in the choroid plexus. Mn-induced cellular overload of Cu at the BCB is due, primarily, to Mn-induced over-expression of CTR1. -- Highlights: ► This study compares the relative role of CTR1 and DMT1 in Cu transport by the BCB. ► Two novel tetracycline-inducible CTR1 and DMT1 expression cell lines are created. ► CTR1, but not DMT1, plays an essential role in transporting Cu by the BCB. ► Mn-induced cellular Cu overload is due to its induction of CTR1 rather than DMT1. ► Induction of CTR1 by Mn in the BCB contributes to an elevated Cu level in the CSF.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish

The teleost swim bladder is assumed a homolog of the tetrapod lung. Both swim bladder and lung are developmental targets of persistent aryl hydrocarbon receptor (AHR) agonists; in zebrafish (Danio rerio) the swim bladder fails to inflate with exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). The mechanism for this effect is unknown, but studies have suggested roles of cytochrome P450 1 (CYP1) and cyclooxygenase 2 (Cox-2) in some Ahr-mediated developmental effects in zebrafish. We determined relationships between swim bladder inflation and CYP1 and Cox-2 mRNA expression in PCB126-exposed zebrafish embryos. We also examined effects on β-catenin dependent transcription, histological effects, and Ahr2 dependence of the effect of PCB126 on swim bladder using morpholinos targeting ahr2. One-day-old embryos were exposed to waterborne PCB126 or carrier (DMSO) for 24 h and then held in clean water until day 4, a normal time for swim bladder inflation. The effects of PCB126 were concentration-dependent with EC{sub 50} values of 1.4 to 2.0 nM for induction of the CYP1s, 3.7 and 5.1 nM (or higher) for cox-2a and cox-2b induction, and 2.5 nM for inhibition of swim bladder inflation. Histological defects included a compaction of the developing bladder. Ahr2-morpholino treatment rescued the effect of PCB126 (5 nM) on swim bladder inflation and blocked induction of CYP1A, cox-2a, and cox-2b. With 2 nM PCB126 approximately 30% of eleutheroembryos failed to inflate the swim bladder, but there was no difference in CYP1 or cox-2 mRNA expression between those embryos and embryos showing inflated swim bladder. Our results indicate that PCB126 blocks swim bladder inflation via an Ahr2-mediated mechanism. This mechanism seems independent of CYP1 or cox-2 mRNA induction but may involve abnormal development of swim bladder cells. -- Highlights: ► PCB126 caused cellular changes in the developing swim bladder. ► Swim bladder inflation was not related to expression of CYP1 or cox-2. ► Failure of swim bladder inflation is mediated via an Ahr2-dependent mechanism. ► PCB126-exposed zebrafish larvae showed upregulation of the oncogene myca.

60 APPLIED LIFE SCIENCES↗