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All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Enabling CCS via Low-temperature Geothermal Energy Integration for Fossil-fired Power Generation

Here, among the key barriers to commercial scale deployment is the cost associated with CO 2 capture. This is particularly true for existing large, fossil-fired assets that account for a large fraction of the electricity generation fleet in developed nations, including the U.S. Fitting conventional combustion technologies with CO 2 capture systems can carry an energy penalty of thirty percent or more, resulting in an increased price of power to the grid, as well as an overall decrease in net plant output. Taken together with the positive growth in demand for electricity, this implies a need for accelerated capital build-out in the power generation markets to accommodate both demand growth and decreased output at retrofitted plants. In this paper, the authors present the results of a study to assess the potential to use geothermal energy to provide boiler feedwater preheating, capturing efficiency improvements designed to offset the losses associated with CO 2 capture. Based on NETL benchmark cases and subsequent analysis of the application using site-specific data from the North Valmy power plant, several cases for CO 2 capture were evaluated. These included geothermally assisted MEA capture, CO2BOLs capture, and stand-alone hybrid power generation, compared with a baseline, no-geothermal case. Based on Case 10, and assuming 2.7 MMlb/h of geothermally sourced 150 ºC water, the parasitic power load associated with MEA capture could be offset by roughly seven percent, resulting in a small (~1 percent) overall loss to net power generation, but at levelized costs of electricity similar to the no-geothermal CCS case. For the CO 2 BOLs case, the availability of 150°C geothermal fluid could allow the facility to not only offset the net power decrease associated with CO 2 BOLs capture alone, but could increase nameplate capacity by two percent. The geothermally coupled CO 2 BOLs case also decreases LCOE by 0.75 ¢/kWh relative to the non-hybrid CO 2 BOLs case, with the improved performance over the MEA case driven by the lower regeneration temperature and associated duty for CO 2 BOLs relative to MEA.

24 POWER TRANSMISSION AND DISTRIBUTION↗
DOE OSTI2017

A Non-condensing Thermal Compression Power Generation System

Organic Rankine cycle (ORC) systems have attracted interest for more than three decades due to advantages in operation at lower working temperature, low maintenance requirements, and relative simplicity (fewer components). In theory, these advantages should make ORC technology more economically attractive for the small and medium power scales (10 kW to 10 MW). Unfortunately, the theoretical promise of ORC systems for power generation has been realized at only a relatively small fraction of the potential market. Although there are a number of reasons for the low utilization of ORC technology, the root cause is directly tied to the relatively low heat-to-power conversion efficiency (2 to 7% typically) and high cost of specially designed expander–generator equipment that is up to 60% of total system cost. The resulting high cost of the power produced just does not make economic sense except in very specialized situations where on-site power is needed but unavailable (at any cost) or where local generation costs are well above regional averages. The overarching objective of the work presented here is to break this paradigm by developing and demonstrating a new harmonic adsorption recuperative power cycle (HARP) system that offers 40% more efficient power generation as compared with a standard ORC system and estimated electric power production costs at very competitive rates below $0.10/kWh.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗
DOE OSTI2022

Kinetic and equilibrium reactions on natural and laboratory generation of thermogenic gases from Type II marine shale

The phenomenon that laboratory pyrolysis experiments produce much wetter gases than those in natural reservoirs is a long-recognized and debated problem in the investigation of natural gases in sedimentary basins. In this study, we explore the discrepancy by pyrolyzing a type II kerogen from the Woodford Shale in Oklahoma, compared with the previous results on the produced natural gases from the Arkoma Basin generated from the same source rock (Liu et al., 2019) with the discussion of gas and isotopic compositions at bulk and position-specific (PS) levels. An improved GC-pyrolysis-GC IRMS method is applied for the determination of PS δ 13 C of propane produced in the pyrolysis of the Woodford Shale at Easy %R o from 0.76 to 3.27. Kinetic and thermodynamic considerations of the chemical and isotopic compositions of the natural and laboratory pyrolysis gases suggest that the generation of light hydrocarbons involves uni-directional cracking reactions, exchange reactions with water, and likely reversible reactions among light hydrocarbons and other H-containing volatiles. After the gas generation in the unconventional Woodford Shale reservoirs, the C 1 -C 4 gases might have approached close to chemical equilibrium of C 1 -C 3 and isotope equilibrium of C 2 -C 1 and C 3 -C 1 pairs at their peak temperatures. The capping H for the generation of C 1 -C 4 in the Woodford Shale gases appears to have experienced at least partial exchange with the water, while that in the pyrolysis gases is only originated from organic-bound compounds with large kinetic isotope effects (KIE). Our findings indicate that elevated compound-specific and PS δ 13 C values of propane in the wet-gas cracking stage are significantly influenced by the breakdown of the thermally stable compounds (e.g., remaining kerogen, residues). A first synthesis of PS δ 13 C and δ 2 H isotopic compositions of propane from this study and the literature data suggests relatively similar isotopic structures of propane precursors in kerogens. Finally, this study demonstrates that PS isotope analysis of propane can contribute to identifying various geological (e.g., maturation, wet-gas cracking, H exchange, diffusion) and biodegradation processes.

58 GEOSCIENCES↗
DOE OSTI2014

Lifetime Increased Cancer Risk in Mice Following Exposure to Clinical Proton Beam–Generated Neutrons

Purpose: To evaluate the life span and risk of cancer following whole-body exposure of mice to neutrons generated by a passively scattered clinical spread-out Bragg peak (SOBP) proton beam. Methods and Materials: Three hundred young adult female FVB/N mice, 152 test and 148 control, were entered into the experiment. Mice were placed in an annular cassette around a cylindrical phantom, which was positioned lateral to the mid-SOBP of a 165-MeV, clinical proton beam. The average distance from the edge of the mid-SOBP to the conscious active mice was 21.5 cm. The phantom was irradiated with once-daily fractions of 25 Gy, 4 days per week, for 6 weeks. The age at death and cause of death (ie, cancer and type vs noncancer causes) were assessed over the life span of the mice. Results: Exposure of mice to a dose of 600 Gy of proton beam–generated neutrons, reduced the median life span of the mice by 4.2% (Kaplan-Meier cumulative survival, P=.053). The relative risk of death from cancer in neutron exposed versus control mice was 1.40 for cancer of all types (P=.0006) and 1.22 for solid cancers (P=.09). For a typical 60 Gy dose of clinical protons, the observed 22% increased risk of solid cancer would be expected to decrease by a factor of 10. Conclusions: Exposure of mice to neutrons generated by a proton dose that exceeds a typical course of radiation therapy by a factor of 10, resulted in a statistically significant increase in the background incidence of leukemia and a marginally significant increase in solid cancer. The results indicate that the risk of out-of-field second solid cancers from SOBP proton-generated neutrons and typical treatment schedules, is 6 to 10 times less than is suggested by current neutron risk estimates.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2020

The effect of lignin degradation products on the generation of pseudo-lignin during dilute acid pretreatment

Pseudo-lignin is an insoluble material that tends to deposit on acidic pretreated fiber surface and negatively impacts the biological conversion of biomass to valued added products. Employing a laboratory generated acidic hydrolysate solution from dilute acid pretreatment of bamboo residues, we sought to seek an improved understanding of pseudo-lignin formation from fragmented carbohydrates. In addition, we also performed experiments to investigate how lignin model compounds interact with carbohydrates en route to pseudo-lignin’s formation. The yields of pseudo-lignin generated from xylose (CXPL) were higher than those generated from glucose (CGPL). Gas chromatography-Mass spectrometry and Foloin-Ciocalteau analysis suggested that there were more aromatic compounds in hydrolyzate during CGPL’s formation. The presence of lignin phenolic model compounds had both a positive and negative effect upon quantitative yields of pseudo-lignin. Gel permeation chromatography and NMR analysis ( 31 P and 2D-HSQC NMR) of the pseudo-lignin samples generated in the presence and absence of 4-hydroxybenzoic acid (4-HA), employed as a lignin model compound, revealed drastic differences in molecular weight, changes in hydroxyl group content, and hydrocarbon bonds, suggesting significant differences in the pseudo-lignin reaction pathways when certain lignin model compounds are present. Finally, our findings demonstrate the effects of both hemicellulose carbohydrate makeup and lignin model compound impact on the formation of pseudo-lignin and its chemical properties, suggesting a potential way to minimize pseudo-lignin formation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

The generation of arbitrary order, non-classical, Gauss-type quadrature for transport applications

A method is presented, based upon the Stieltjes method (1884), for the determination of non-classical Gauss-type quadrature rules, and the associated sets of abscissae and weights. The method is then used to generate a number of quadrature sets, to arbitrary order, which are primarily aimed at deterministic transport calculations. The quadrature rules and sets detailed include arbitrary order reproductions of those presented by Abu-Shumays in [4,8] (known as the QR sets, but labelled QRA here), in addition to a number of new rules and associated sets; these are generated in a similar way, and we label them the QRS quadrature sets. The method presented here shifts the inherent difficulty (encountered by Abu-Shumays) associated with solving the non-linear moment equations, particular to the required quadrature rule, to one of the determination of non-classical weight functions and the subsequent calculation of various associated inner products. Once a quadrature rule has been written in a standard form, with an associated weight function having been identified, the calculation of the required inner products is achieved using specific variable transformations, in addition to the use of rapid, highly accurate quadrature suited to this purpose. The associated non-classical Gauss quadrature sets can then be determined, and this can be done to any order very rapidly. In this paper, instead of listing weights and abscissae for the different quadrature sets detailed (of which there are a number), the MATLAB code written to generate them is included as Appendix D. The accuracy and efficacy (in a transport setting) of the quadrature sets presented is not tested in this paper (although the accuracy of the QRA quadrature sets has been studied in [12,13]), but comparisons to tabulated results listed in [8] are made. When comparisons are made with one of the azimuthal QRA sets detailed in [8], the inherent difficulty in the method of generation, used there, becomes apparent, with the highest order tabulated sets showing unexpected anomalies. Although not in an actual transport setting, the accuracy of the sets presented here is assessed to some extent, by using them to approximate integrals (over an octant of the unit sphere) of various high order spherical harmonics. When this is done, errors in the tabulated QRA sets present themselves at the highest tabulated orders, whilst combinations of the new QRS quadrature sets offer some improvements in accuracy over the original QRA sets. Finally, in order to offer a quick, visual understanding of the various quadrature sets presented, when combined to give product sets for the purposes of integrating functions confined to the surface of a sphere, three-dimensional representations of points located on an octant of the unit sphere (as in [8,12]) are shown.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2016

Constrained approximation of effective generators for multiscale stochastic reaction networks and application to conditioned path sampling

Efficient analysis and simulation of multiscale stochastic systems of chemical kinetics is an ongoing area for research, and is the source of many theoretical and computational challenges. In this paper, we present a significant improvement to the constrained approach, which is a method for computing effective dynamics of slowly changing quantities in these systems, but which does not rely on the quasi-steady-state assumption (QSSA). The QSSA can cause errors in the estimation of effective dynamics for systems where the difference in timescales between the “fast” and “slow” variables is not so pronounced. This new application of the constrained approach allows us to compute the effective generator of the slow variables, without the need for expensive stochastic simulations. This is achieved by finding the null space of the generator of the constrained system. For complex systems where this is not possible, or where the constrained subsystem is itself multiscale, the constrained approach can then be applied iteratively. This results in breaking the problem down into finding the solutions to many small eigenvalue problems, which can be efficiently solved using standard methods. Since this methodology does not rely on the quasi steady-state assumption, the effective dynamics that are approximated are highly accurate, and in the case of systems with only monomolecular reactions, are exact. We will demonstrate this with some numerics, and also use the effective generators to sample paths of the slow variables which are conditioned on their endpoints, a task which would be computationally intractable for the generator of the full system.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2024

SDYN-GANs: Adversarial learning methods for multistep generative models for general order stochastic dynamics

We introduce adversarial learning methods for data-driven generative modeling of dynamics of nth-order stochastic systems. Our approach builds on Generative Adversarial Networks (GANs) with generative model classes based on stable m-step stochastic numerical integrators. From observations of trajectory samples, we introduce methods for learning long-time predictors and stable representations of the dynamics. Our approaches use discriminators based on Maximum Mean Discrepancy (MMD), training protocols using both conditional and marginal distributions, and methods for learning dynamic responses over different time-scales. We show how our approaches can be used for modeling physical systems to learn force-laws, damping coefficients, and noise-related parameters. Our adversarial learning approaches provide methods for obtaining stable generative models for dynamic tasks including long-time prediction and developing simulations for stochastic systems.

• Artificial intelligence (AI) / machine learning ↗
DOE OSTI2022

Projected network performance for next-generation xenon monitoring systems

Next-generation radioxenon monitoring systems are reaching maturity and are expected to improve certain aspects of performance in verifying the absence of nuclear tests. To predict the improvement in detecting and locating nuclear releases, thousands of releases all over the globe were simulated and the global detection probability was calculated. This was done for the International Monitoring System network of noble gas samplers as it currently exists (25 certified stations), and how it would be for potential future network sizes of 39 and 79 stations. The probability of detection was calculated for releases ranging from 10 10 Bq to 10 16 Bq of 133 Xe and presented as coverage maps and global integrals for both current and next-generation monitoring systems. Similarly, the number of detecting stations and the number of detecting samples were tabulated to elucidate the possibilities for enhanced location capability. Improvements in global detection coverage are maximized at different release sizes in a way that depends on the station density. For example, for releases of 3×10 14 Bq and 39 stations, the detection probability would rise from 60% to 70% with next-generation systems, while for releases of 10 13 Bq and 79 stations, it would rise from 37% to 52%. Achieving an average of two detecting stations requires a 1015 Bq release for a 39-station network and a 10 14 Bq release for a 79-station network. The largest impact of using next-generation systems may be the confidence, failure tolerance, and location capability that arise from obtaining multiple samples associated with a single release event.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2019

Crystal structure of F95Q epi-isozizaene synthase, an engineered sesquiterpene cyclase that generates biofuel precursors β- and γ-curcumene

The saturated hydrocarbon bisabolane is a diesel fuel substitute that can be derived from sesquiterpene precursors bisabolene or curcumene. These sesquiterpenes are generated from farnesyl diphosphate in reactions catalyzed by eponymous terpenoid cyclases, but they can also be generated by engineered terpenoid cyclases in which cyclization cascades have been reprogrammed by mutagenesis. Here, we describe the X-ray crystal structure determination of F95Q epi-isozizaene synthase (EIZS), in which the new activity of curcumene biosynthesis has been introduced and the native activity of epi-isozizaene biosynthesis has been suppressed. F95Q EIZS generates β- and γ-curcumene regioisomers with greater than 50% yield. Structural analysis of the closed active site conformation, stabilized by the binding of 3 Mg 2+ ions, inorganic pyrophosphate, and the benzyltriethylammonium cation, reveals a product-like active site contour that serves as the cyclization template. Remolding the active site contour to resemble curcumene instead of epi-isozizaene is the principal determinant of the reprogrammed cyclization cascade. Intriguingly, an ordered water molecule comprises part of the active site contour. Additionally, this water molecule may also serve as a final proton acceptor, along with inorganic pyrophosphate, in the generation of curcumene regioisomers; it may also contribute to the formation of sesquiterpene alcohols identified as minor side products. Thus, the substitution of polar side chains for nonpolar side chains in terpenoid cyclase active sites can result in the stabilization of bound water molecules that, in turn, can serve template functions in isoprenoid cyclization reactions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Generation of H{sub 2} and CO by solar thermochemical splitting of H{sub 2}O and CO{sub 2} by employing metal oxides

Generation of H{sub 2} and CO by splitting H{sub 2}O and CO{sub 2} respectively constitutes an important aspect of the present-day concerns with energy and environment. The solar thermochemical route making use of metal oxides is a viable means of accomplishing these reduction reactions. The method essentially involves reducing a metal oxide by heating and passing H{sub 2}O or CO{sub 2} over the nonstoichiometric oxide to cause reverse oxidation by abstracting oxygen from H{sub 2}O or CO{sub 2}. While ceria, perovskites and other oxides have been investigated for this purpose, recent studies have demonstrated the superior performance of perovskites of the type Ln{sub 1−x}A{sub x}Mn{sub 1−y}M{sub y}O{sub 3} (Ln=rare earth, A=alkaline earth, M=various +2 and +3 metal ions), in the thermochemical generation of H{sub 2} and CO. We present the important results obtained hitherto to point out how the alkaine earth and the Ln ions, specially the radius of the latter, determine the performance of the perovskites. The encouraging results obtained are exemplefied by Y{sub 0.5}Sr{sub 0.5}MnO{sub 3} which releases 483 µmol/g of O{sub 2} at 1673 K and produces 757 µmol/g of CO from CO{sub 2} at 1173 K. The production of H{sub 2} from H{sub 2}O is also quite appreciable. Modification of the B site ion of the perovskite also affects the performance. In addition to perovskites, we present the generation of H{sub 2} based on the Mn{sub 3}O{sub 4}/NaMnO{sub 2} cycle briefly. - Graphical abstract: Ln{sub 0.5}A{sub 0.5}Mn{sub 1−x}M{sub x}O{sub 3} (Ln=lanthanide; A=Ca, Sr; M=Al, Ga, Sc, Mg, Cr, Fe, Co) perovskites are employed for the two step thermochemical splitting of CO{sub 2} and H{sub 2}O for the generation of CO and H{sub 2}. - Highlights: • Perovskite oxides based on Mn are ideal for the two-step thermochemical splitting of CO{sub 2} and H{sub 2}O. • In Ln{sub 1−x}A{sub x}MnO{sub 3} perovskite (Ln=rare earth, A=alkaline earth) both Ln and A ions play major roles in the thermochemical process. • H{sub 2}O splitting is also achieved by the use of the Mn{sub 3}O{sub 4}-sodium carbonate system. • Thermochemical splitting of CO{sub 2} and H{sub 2}O using perovskite oxides is explained. • Mn based perovskites.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2013

Graphene oxide functionalized with methylene blue and its performance in singlet oxygen generation

Graphical abstract: - Highlights: • Adsorption of methylene blue (MB) on graphene oxide (GO). • Characterization of graphene oxide–methylene blue nanocomposite (MB–GO). • Examination of MB–GO efficiency in singlet oxygen generation (SOG). • MB–GO performs higher SOG efficiency than pristine MB. - Abstract: Due to unique electronic, mechanical, optical and structural properties, graphene has shown promising applications in many fields, including biomedicine. One of them is noninvasive anticancer therapy – photodynamic therapy (PDT), where singlet oxygen (SO), generated under the irradiation of light with appropriate wavelengths, kills cancer cells. In this study, authors report graphene oxide (GO) noncovalent functionalization with methylene blue (MB). MB molecules underwent adsorption on the surface of GO. Detailed characterization of the obtained material was carried out with UV–vis spectroscopy, Raman spectroscopy, FT-IR spectroscopy, and confocal laser scanning microscopy. Furthermore, its performance in singlet oxygen generation (SOG) under irradiation of laser with excitation wavelengths of 785 nm was investigated. Interestingly, GO functionalized with MB (MB–GO) showed enhanced efficiency in singlet oxygen generation compared to pristine MB. The efficiency in SOG was detected by photobleaching of 9,10-anthracenediyl-bis(methylene)dimalonic acid (ABMDMA). These results indicate the material is promising in PDT anticancer therapy and further in vitro and in vivo studies are required.

36 MATERIALS SCIENCE↗
DOE OSTI2023

Comparison of forward and inverse cam generation methods for the design of cam-linkage mechanisms

This paper presents a comparison between the forward and inverse cam generation methods applied to the design of a multi-lobed cam-rocker slider mechanism for function generation. In the forward method, the cam profile is specified directly and then the linkage output is determined using kinematics. In the inverse method, the trajectory of the output link is specified first and then the cam profile is determined using inverse linkage kinematics. First, the cam-linkage mechanism is introduced, and relevant kinematic equations are presented. Then, the cam generation methods are thoroughly explained. Here, the two cam generation methods are applied to a case study of a hydraulic motor using a multi-lobed cam and multiple linkage mechanisms. While the forward method has direct control of the cam shape, the inverse method has direct control of the linkage output and offers an advantage in calculation speed. For the mechanism selected, the cam designed with the inverse method achieved a reduction of at least 50.97% in the torque ripple when compared to the cam designed with the forward method.

42 ENGINEERING↗
DOE OSTI2021

Methane generation from low-maturity coals and shale source rocks at low temperatures (80–120 °C) over 14–38 months

This study contributes long-term (14 to 38 months) experimental evidence for geocatalytically mediated methanogenesis in immature to early mature shale and coal source rocks at temperatures from 80 to 120 °C. Borosilicate glass tubes with pre-outgassed coal and shale source rock chips and water were sealed under vacuum, sterilized, heated isothermally, and finally opened in connection with a vacuum line where headspace gases methane (CH 4 ) and carbon dioxide (CO 2 ) were collected. The possibility of admitting pre-existing CH 4 from closed pores into product gases during heating experiments was evaluated by comparative ball milling of original and heated rock chips, followed by quantitation of released gases with a novel closed-circuit laser-based SARAD RTM2200 gas detector system with sub-µmol sensitivity. The yields of produced CH 4 from individual source rocks were corrected by subtracting the amounts of pre-existing CH 4 from formerly closed pores in original source rocks that had leaked during long-term heating. Different shales and coals express contrasting propensities to geocatalytically generate CH 4 and CO 2 , with CH 4 yields ranging from 0.1 to 5.5 µmol g-1 total organic carbon (TOC). CH 4 yields from two petrographically different samples of Springfield Coal with comparable thermal maturity suggest that liptinite expresses a far higher propensity for methanogenesis, but liberates less CO 2 than vitrinite. Shale from the Second White Specks Formation generated approximately 10 times more CH 4 than New Albany Shale per g of TOC, further suggesting complex controls on CH 4 generation during catalytic methanogenesis. Higher temperature can enhance the activities of catalytic methanogenesis. Here, the extrapolation of laboratory-based reaction rates to natural conditions in organic-rich buried sediments suggests that geocatalytic methanogenesis can be fast enough in some source rocks to generate economically sizeable gas plays from immature to early mature source rocks over geologic time.

03 NATURAL GAS↗
DOE OSTI2015

Array-based Hierarchical Mesh Generation in Parallel

In this paper, we describe an array-based hierarchical mesh generation capability through uniform refinement of unstructured meshes for efficient solution of PDE's using finite element methods and multigrid solvers. A multi-degree, multi-dimensional and multi-level framework is designed to generate the nested hierarchies from an initial mesh that can be used for a number of purposes such as multi-level methods to generating large meshes. The capability is developed under the parallel mesh framework “Mesh Oriented dAtaBase” a.k.a MOAB. We describe the underlying data structures and algorithms to generate such hierarchies and present numerical results for computational efficiency and mesh quality. In conclusion, we also present results to demonstrate the applicability of the developed capability to a multigrid finite-element solver.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2024

Enhancing power grid resilience to winter storms via generator winterization with equity considerations

Here we develop two-stage stochastic programming models for generator winterization that enhance power grid resilience while incorporating social equity. The first stage in our models captures the investment decisions for generator winterization, and the second stage captures the operation of a degraded power grid, with the objective of minimizing load shed and social inequity. To incorporate equity into our models, we propose a concept called adverse effect probability that captures the disproportionate effects of power outages on communities with varying vulnerability levels. Grid operations are modeled using DC power flow, and equity is captured through mean or maximum adverse effects experienced by communities. We apply our models to a synthetic Texas power grid, using winter storm scenarios created from the generator outage data from the 2021 Texas winter storm. Our extensive numerical experiments show that more equitable outcomes, in the sense of reducing adverse effects experienced by vulnerable communities during power outages, are achievable with no impact on total load shed through investing in winterization of generators in different locations and capacities.

24 POWER TRANSMISSION AND DISTRIBUTION↗
DOE OSTI2013

A novel synthetic analog of militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells

A synthetic Militarin analog-1[(2R,3R,4R,5R)-1,6-bis(4-(2,4,4-trimethylpentan-2-yl)phenoxy) hexane-2,3,4,5-tetraol] is a novel derivative of constituents from Cordyceps militaris, which has been used to treat a variety of chronic diseases including inflammation, diabetes, hyperglycemia and cancers. Here, we report for the first time the synthesis of Militarin analog-1 (MA-1) and the apoptotic mechanism of MA-1 against human lung cancer cell lines. Treatment with MA-1 significantly inhibited the viability of 3 human lung cancer cell lines. The inhibition of viability and growth in MA-1-treated A549 cells with an IC{sub 50} of 5 μM were mediated through apoptosis induction, as demonstrated by an increase in DNA fragmentation, sub-G{sub 0}/G{sub 1}-DNA fraction, nuclear condensation, and phosphatidylserine exposure. The apoptotic cell death caused mitochondrial membrane permeabilization through regulation of expression of the Bcl-2 family proteins, leading to cytochrome c release in a time-dependent manner. Subsequently, the final stage of apoptosis, activation of caspase-9/-3 and cleavage of poly (ADP ribose) polymerase, was induced. Furthermore, A549 lung cancer cells were more responsive to MA-1 than a bronchial epithelial cell line (BEAS-2B), involving the rapid generation of reactive oxygen species (ROS), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation. The pharmacological inhibition of ROS generation and JNK/p38 MAPK exhibited attenuated DNA fragmentation in MA-1-induced apoptosis. Oral administration of MA-1 also retarded growth of A549 orthotopic xenografts. In conclusion, the present study indicates that the new synthetic derivative MA-1 triggers mitochondrial apoptosis through ROS generation and regulation of MAPKs and may be a potent therapeutic agent against human lung cancer. - Highlights: • We report a novel synthesized derivative, militarin analog-1 (MA-1). • MA-1-induced cancer cell death was triggered by the ROS generation through MAPKs. • The MA-1-induced cell death was also modulated by the mitochondria-mediated pathway. • The apoptotic cancer cell death by MA-1 was also exhibited in orthotopic xenografts. • Our findings suggest MA-1 as a clinically useful agent for human lung cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Osimertinib induces autophagy and apoptosis via reactive oxygen species generation in non-small cell lung cancer cells

Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells. The OSI-induced expression of LC3-II was further increased when combined treatment with chloroquine (CQ), an autophagy inhibitor, and the mRFP-EGFP-LC3 plasmid-transfected cells exposed to OSI led to the production of more red-fluorescent puncta than green-fluorescent puncta, indicating OSI induced autophagic flux in the NSCLC cells. Knockdown of EGFR showed no effect on the OSI-induced expression of LC3-II in NCI-H1975 cells. In addition, OSI increased reactive oxygen species (ROS) generation and scavenge of ROS via pretreatment with N-acetyl-L-cysteine (NAC), catalase (CAT), or vitamin E (Vita E) significantly inhibited OSI-induced the accumulations of cytoplasmic vacuoles, the expression of LC3-II, as well as the formation of GFP-LC3 puncta. Combinative treatment with CQ could not remarkably change the OSI-induced cell viability decrease, whereas the OSI-induced cell viability decrease and apoptosis could be reversed through pretreatment with NAC, CAT, and Vita E, respectively. Taken together, this is the first report that OSI induces an accompanied autophagy and the generation of ROS is critical for the OSI-induced autophagy, cell viability decrease, and apoptosis in NSCLC cells. - Highlights: • Osimertinib induced the expressions of cytoplasmic vacuoles and autophagic markers in different cancer cells. • Osimertinib induced autophagic flux in NSCLC NCI-H1975 and HCC827 cell lines. • ROS generation contributed to osimertinib-induced cytoplasmic vacuoles, autophagy, cell viability decrease, and apoptosis.

60 APPLIED LIFE SCIENCES↗