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Independent Technical Assessment of NASA and External Quantum Sensing Capability

- The Subject Matter Experts in the Sensors & Instrumentation Quantum Sensing Community of Practice (CoP) requested an independent technical assessment of the agency's capabilities in QS to understand NASA's internal needs and competencies related to QS and compare agency capabilities with those available externally including industry, academia, and other government agencies. - The outcomes of the assessment will help the agency in establishing appropriate strategies and investments to develop and maintain the state-of-the-art sensing competence and capabilities required to meet the agency’s future needs. - NASA Engineering and Safety Center Review Board approved the assessment request and assigned NASA Technical Fellow to lead and conduct the assessment by engaging NASA Centers, NASA HQ and an independent, non-commercial, and highly credible Quantum Sensing Experts from Academia, Department of Defense, other Government Agencies. The assessment duration is for one year, starting October 2021 and ending December 2022.

Independent Technical Assessment↗
DOE OSTI2016

Luminescent Gold Nanoparticles with Size-Independent Emission

Size-independent emission has been widely observed for ultrasmall thiolated gold nanoparticles (AuNPs) but our understanding of the photoluminescence mechanisms of noble metals on the nanoscale has remained limited. In this paper, we report how the emission wavelength of a AuNP and the local binding geometry of a thiolate ligand (glutathione) on the AuNP are correlated, as these AuNPs emit at different wavelengths in spite of their identical size (ca. 2.5 nm). By using circular dichroism, X-ray absorption, and fluorescence spectroscopy, we found that a high Au–S coordination number (CN) and a high surface coverage resulted in strong Au I –ligand charge transfer, a chiral conformation, and 600 nm emission, whereas a low Au–S CN and a low surface coverage led to weak charge transfer, an achiral conformation, and 810 nm emission. These two size-independent emissions can be integrated into one single 2.5 nm AuNP by fine-tuning of the surface coverage; a ratiometric pH response was then observed owing to strong energy transfer between two emission centers, opening up new possibilities for the design of ultrasmall ratiometric pH nanoindicators.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Model-independent measurement of the Higgs boson associated production with two jets and decaying to a pair of W bosons in proton-proton collisions at $\sqrt{s}=13$ TeV

A model-independent measurement of the differential production cross section of the Higgs boson decaying into a pair of W bosons, with a final state including two jets produced in association, is presented. In the analysis, events are selected in which the decay products of the two W bosons consist of an electron, a muon, and missing transverse momentum. The model independence of the measurement is maximized by employing a discriminating variable, developed through machine learning, that is agnostic to the signal hypothesis. The analysis is based on proton-proton collision data at $\sqrt{s}=13$ TeV collected with the CMS detector from 2016–2018, corresponding to an integrated luminosity of 138 fb −1 . The production cross section is measured as a function of the difference in azimuthal angle between the two jets. The differential cross section measurements are used to constrain Higgs boson couplings within the standard model effective field theory framework.

Hadron-Hadron Scattering↗
DOE OSTI2024

Model-independent search for pair production of new bosons decaying into muons in proton-proton collisions at $\sqrt{s}$ = 13 TeV

The results of a model-independent search for the pair production of new bosons within a mass range of 0.21 < m < 60 GeV, are presented. This study utilizes events with a four-muon final state. We use two data sets, comprising 41.5 fb −1 and 59.7 fb −1 of proton-proton collisions at $\sqrt{s}$ = 13 TeV, recorded in 2017 and 2018 by the CMS experiment at the CERN LHC. The study of the 2018 data set includes a search for displaced signatures of a new boson within the proper decay length range of 0 < cτ < 100 mm. Our results are combined with a previous CMS result, based on 35.9 fb −1 of proton-proton collisions at $\sqrt{s}$ = 13 TeV collected in 2016. No significant deviation from the expected background is observed. Results are presented in terms of a model-independent upper limit on the product of cross section, branching fraction, and acceptance. The findings are interpreted across various benchmark models, such as an axion-like particle model, a vector portal model, the next-to-minimal supersymmetric standard model, and a dark supersymmetric scenario, including those predicting a non-negligible proper decay length of the new boson. In all considered scenarios, substantial portions of the parameter space are excluded, expanding upon prior results.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
DOE OSTI2018

Transarterial Radioembolization Following Chemoembolization for Unresectable Hepatocellular Carcinoma: Response Based on Apparent Diffusion Coefficient Change is an Independent Predictor for Survival

PurposeTo evaluate whether response based on contrast-enhanced magnetic resonance imaging (MRI) and apparent diffusion coefficient (ADC) change at diffusion-weighted MRI after transarterial radioembolization (TARE) can predict survival, in patients with prior transarterial chemoembolization with drug-eluting beads (DEB-TACE) for hepatocellular carcinoma (HCC).MethodsWe identified all patients who received DEB-TACE prior to TARE for HCC between 2007 and 2016. Response on MRI was determined by modified RECIST (mRECIST) and ADC change relative to pre-TARE imaging (ADCratio). Kaplan–Meier and log-rank tests were used to correlate the response/disease and treatment variables to overall survival. Multivariable Cox regression models were used to correct for confounders.ResultsA total of 29 consecutive patients were included. Univariable analysis showed that response determined by mRECIST was a nonsignificant predictor of survival (p = 0.057), and response determined by ADCratio was a significant predictor of survival (p = 0.011). Number of prior DEB-TACE procedures (p = 0.037), female gender (p < 0.001) and BCLC C (p = 0.03) were related to worse survival. The number of prior DEB-TACE procedure was significantly higher in non-responders determined by ADCratio (p = 0.028). Multivariable analyses showed that response based on ADCratio was an independent predictor of survival (p = 0.041).ConclusionADCratio following TARE is an independent predictor for survival in patients who previously underwent DEB-TACE for HCC.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Flux Large Deviations of Independent and Reacting Particle Systems, with Implications for Macroscopic Fluctuation Theory

We consider a system of independent particles and a system of reacting particles on a discrete state space. For the independent case, we rigorously prove a dynamic large-deviation principle for the empirical measure-integrated flux pair, taking the one-way fluxes rather than net fluxes into account. We prove the large deviations under deterministic initial conditions, and under random initial conditions satisfying a large-deviation principle. We formally calculate similar one-way flux large deviations for the more general reacting particles case. Next, we use these results to derive a number of principles from Macroscopic Fluctuation Theory like time-reversal principles and generalised gradient structures.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2018

On the Size Dependence of Molar and Specific Properties of Independent Nano-phases and Those in Contact with Other Phases

Nano-materials are materials with at least one nano-phase. A nano-phase is a phase with at least one of its dimensions below 100 nm. It is shown here that nano-phases have at least 1% of their atoms along their surface layer. The ratio of surface atoms is proportional to the specific surface area of the phase, defined as the ratio of its surface area to its volume. Each specific/molar property has its bulk value and its surface value for the given phase, being always different, as the energetic states of the atoms in the bulk and in the surface layer of a phase are different. The average specific/molar property of a nano-phase is modeled here as a linear combination of the bulk and surface values of the same property, scaled with the ratio of the surface atoms. That makes the performance of all nano-phases proportional to their specific surface area. As the characteristic size of the nano-phase is inversely proportional to its specific surface area, all specific/molar properties of nano-phases are inversely proportional to the characteristic size of the phase. This is applied to the size dependence of the molar Gibbs energy of the nano-phase, which appears to be in agreement with the thermodynamics of Gibbs. This agreement proves the general validity of the present model on the size dependence of the specific/molar properties of independent nano-phases. It is shown that the properties of nano-phases are different for independent nano-phases (surrounded only by their equilibrium vapor phase) and for nano-phases in multi-phase situations, such as a liquid nano-droplet in the sessile drop configuration.

77 NANOSCIENCE AND NANOTECHNOLOGY↗
DOE OSTI2013

Momentum-independent reflectionless transmission in the non-Hermitian time-reversal symmetric system

We theoretically study the non-Hermitian systems, the non-Hermiticity of which arises from the unequal hopping amplitude (UHA) dimers. The distinguishing features of these models are that they have full real spectra if all of the eigenvectors are time-reversal (T) symmetric rather than parity-time-reversal (PT) symmetric, and that their Hermitian counterparts are shown to be an experimentally accessible system, which have the same topological structures as that of the original ones but modulated hopping amplitudes within the unbroken region. Under the reflectionless transmission condition, the scattering behavior of momentum-independent reflectionless transmission (RT) can be achieved in the concerned non-Hermitian system. This peculiar feature indicates that, for a certain class of non-Hermitian systems with a balanced combination of the RT dimers, the defects can appear fully invisible to an outside observer. -- Highlights: •We investigate the non-Hermitian system with time reversal symmetry. •The Hermitian counterpart is experimentally accessible system. •The behavior of momentum-independent reflectionless transmission can be achieved. •A balanced combination of reflectionless transmission dimers leads to invisibility. •It paves an alternative way for the design of invisible cloaking devices.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2019

Background independent quantum field theory and gravitating vacuum fluctuations

The scale dependent effective average action for quantum gravity complies with the fundamental principle of Background Independence. Ultimately the background metric it formally depends on is selected self-consistently by means of a tadpole condition, a generalization of Einstein’s equation. Self-consistent background spacetimes are scale dependent, and therefore “going on-shell” at the points along a given renormalization group (RG) trajectory requires understanding two types of scale dependencies: the (familiar) direct one carried by the off-shell action functional, and an equally important indirect one related to the continual re-adjustment of the background geometry. This paper is devoted to a careful delineation and analysis of certain general questions concerning the indirect scale dependence, as well as a detailed explicit investigation of the case where the self-consistent metrics are determined predominantly by the RG running of the cosmological constant. Mathematically, the object of interest is the spectral flow induced by the background Laplacian which, on-shell, acquires an explicit scale dependence. Among other things, it encodes the complete information about the specific set of field modes which, at any given scale, are the degrees of freedom constituting the respective effective field theory. For a large class of RG trajectories (Type IIIa) we discover a seemingly paradoxical behavior that differs substantially from the off-shell based expectations: A Background Independent theory of (matter coupled) quantum gravity looses rather than gains degrees of freedom at increasing energies. As an application, we investigate to what extent it is possible to reformulate the exact theory in terms of matter and gravity fluctuations on a rigid flat space. It turns out that, in vacuo, this “rigid picture” breaks down after a very short RG time already (less than one decade of scales) because of a “scale horizon” that forms. Furthermore, we critically reanalyze and refute the frequent claim that the huge energy densities one obtains in standard quantum field theory by summing up to zero-point energies imply a naturalness problem for the observed small value of the cosmological constant.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
DOE OSTI2013

PARP-2 regulates cell cycle-related genes through histone deacetylation and methylation independently of poly(ADP-ribosyl)ation

Highlights: ► PARP-2 acts as a transcription co-repressor independently of PARylation activity. ► PARP-2 recruits HDAC5, 7, and G9a and generates repressive chromatin. ► PARP-2 is recruited to the c-MYC promoter by DNA-binding factor YY1. ► PARP-2 represses cell cycle-related genes and alters cell cycle progression. -- Abstract: Poly(ADP-ribose) polymerase-2 (PARP-2) catalyzes poly(ADP-ribosyl)ation (PARylation) and regulates numerous nuclear processes, including transcription. Depletion of PARP-2 alters the activity of transcription factors and global gene expression. However, the molecular action of how PARP-2 controls the transcription of target promoters remains unclear. Here we report that PARP-2 possesses transcriptional repression activity independently of its enzymatic activity. PARP-2 interacts and recruits histone deacetylases HDAC5 and HDAC7, and histone methyltransferase G9a to the promoters of cell cycle-related genes, generating repressive chromatin signatures. Our findings propose a novel mechanism of PARP-2 in transcriptional regulation involving specific protein–protein interactions and highlight the importance of PARP-2 in the regulation of cell cycle progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Unexpected T cell regulatory activity of anti-histone H1 autoantibody: Its mode of action in regulatory T cell-dependent and -independent manners

Highlights: ► Anti-histone H1 autoantibody (anti-H1) acts on T cells to inhibit their activation. ► Anti-H1 suppresses T cell activation in Treg cell-dependent and -independent manners. ► Suboptimal dose of anti-H1 enhances suppressor function of Treg cells. ► High dose of anti-H1 directly inhibits T cell receptor signaling. -- Abstract: Induction of anti-nuclear antibodies against DNA or histones is a hallmark of autoimmune disorders, but their actual contribution to disease predisposition remains to be clarified. We have previously reported that autoantibodies against histone H1 work as a critical graft survival factor in a rat model of tolerogeneic liver transplantation. Here we show that an immunosuppressive anti-histone H1 monoclonal antibody (anti-H1 mAb) acts directly on T cells to inhibit their activation in response to T cell receptor (TCR) ligation. Intriguingly, the T cell activation inhibitory activity of anti-H1 mAb under suboptimal dosages required regulatory T (Treg) cells, while high dose stimulation with anti-H1 mAb triggered a Treg cell-independent, direct negative regulation of T cell activation upon TCR cross-linking. In the Treg cell-dependent mode of immunosuppressive action, anti-H1 mAb did not induce the expansion of CD4{sup +}Foxp3{sup +} Treg cells, but rather potentiated their regulatory capacity. These results reveal a previously unappreciated T cell regulatory role of anti-H1 autoantibody, whose overproduction is generally thought to be pathogenic in the autoimmune settings.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

AS-2, a novel inhibitor of p53-dependent apoptosis, prevents apoptotic mitochondrial dysfunction in a transcription-independent manner and protects mice from a lethal dose of ionizing radiation

Highlights: • A bidentate HQ derivative, AS-2, suppresses p53-dependent apoptosis by DNA damage. • AS-2 does not significantly affect nuclear p53 response. • UV-excited blue emission of AS-2 clearly showed its extranuclear localization. • AS-2 prevents mitochondrial dysfunction despite the increase of mitochondrial p53. • AS-2 protects mice from a radiation dose that causes lethal hematopoietic syndrome. - Abstract: In a previous study, we reported that some tetradentate zinc(II) chelators inhibit p53 through the denaturation of its zinc-requiring structure but a chelator, Bispicen, a potent inhibitor of in vitro apoptosis, failed to show any efficient radioprotective effect against irradiated mice because the toxicity of the chelator to mice. The unsuitability of using tetradentate chelators as radioprotectors prompted us to undertake a more extensive search for p53-inhibiting agents that are weaker zinc(II) chelators and therefore less toxic. Here, we show that an 8-hydroxyquinoline (8HQ) derivative, AS-2, suppresses p53-dependent apoptosis through a transcription-independent mechanism. A mechanistic study using cells with different p53 characteristics revealed that the suppressive effect of AS-2 on apoptosis is specifically mediated through p53. In addition, AS-2 was less effective in preventing p53-mediated transcription-dependent events than pifithrin-μ (PFTμ), an inhibitor of transcription-independent apoptosis by p53. Fluorescence visualization of the extranuclear distribution of AS-2 also supports that it is ineffective on the transcription-dependent pathway. Further investigations revealed that AS-2 suppressed mitochondrial apoptotic events, such as the mitochondrial release of intermembrane proteins and the loss of mitochondrial membrane potential, although AS-2 resulted in an increase in the mitochondrial translocation of p53 as opposed to the decrease of cytosolic p53, and did not affect the apoptotic interaction of p53 with Bcl-2. AS-2 also protected mice that had been exposed to a lethal dose of ionizing radiation. Our findings indicate that some types of bidentate 8HQ chelators could serve as radioprotectors with no substantial toxicity in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome

Highlights: • Glycolytic markers are highly expressed in triple negative breast cancers. • Lactate/H{sup +} symporter MCT4 demonstrated the strongest deleterious impact on survival. • MCT4 should serve as a new prognostic factor in node-negative breast cancers. - Abstract: Background: {sup 18}Fluor-deoxy-glucose PET-scanning of glycolytic metabolism is being used for staging in many tumors however its impact on prognosis has never been studied in breast cancer. Methods: Glycolytic and hypoxic markers: glucose transporter (GLUT1), carbonic anhydrase IX (CAIX), monocarboxylate transporter 1 and 4 (MCT1, 4), MCT accessory protein basigin and lactate-dehydrogenase A (LDH-A) were assessed by immunohistochemistry in two cohorts of breast cancer comprising 643 node-negative and 127 triple negative breast cancers (TNBC) respectively. Results: In the 643 node-negative breast tumor cohort with a median follow-up of 124 months, TNBC were the most glycolytic (≈70%), followed by Her-2 (≈50%) and RH-positive cancers (≈30%). Tumoral MCT4 staining (without stromal staining) was a strong independent prognostic factor for metastasis-free survival (HR = 0.47, P = 0.02) and overall-survival (HR = 0.38, P = 0.002). These results were confirmed in the independent cohort of 127 cancer patients. Conclusion: Glycolytic markers are expressed in all breast tumors with highest expression occurring in TNBC. MCT4, the hypoxia-inducible lactate/H{sup +} symporter demonstrated the strongest deleterious impact on survival. We propose that MCT4 serves as a new prognostic factor in node-negative breast cancer and can perhaps act soon as a theranostic factor considering the current pharmacological development of MCT4 inhibitors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Omeprazole induces NAD(P)H quinone oxidoreductase 1 via aryl hydrocarbon receptor-independent mechanisms: Role of the transcription factor nuclear factor erythroid 2–related factor 2

Activation of the aryl hydrocarbon receptor (AhR) transcriptionally induces phase I (cytochrome P450 (CYP) 1A1) and phase II (NAD(P)H quinone oxidoreductase 1 (NQO1) detoxifying enzymes. The effects of the classical and nonclassical AhR ligands on phase I and II enzymes are well studied in human hepatocytes. Additionally, we observed that the proton pump inhibitor, omeprazole (OM), transcriptionally induces CYP1A1 in the human adenocarcinoma cell line, H441 cells via AhR. Whether OM activates AhR and induces the phase II enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1), in fetal primary human pulmonary microvascular endothelial cells (HPMEC) is unknown. Therefore, we tested the hypothesis that OM will induce NQO1 in HPMEC via the AhR. The concentrations of OM used in our experiments did not result in cytotoxicity. OM activated AhR as evident by increased CYP1A1 mRNA expression. However, contrary to our hypothesis, OM increased NQO1 mRNA and protein via an AhR-independent mechanism as AhR knockdown failed to abrogate OM-mediated increase in NQO1 expression. Interestingly, OM activated Nrf2 as evident by increased phosphoNrf2 (S40) expression in OM-treated compared to vehicle-treated cells. Furthermore, Nrf2 knockdown abrogated OM-mediated increase in NQO1 expression. In conclusion, we provide evidence that OM induces NQO1 via AhR-independent, but Nrf2-dependent mechanisms. - Highlights: • We investigated whether omeprazole induces NQO1 in human fetal lung cells. • Omeprazole induces the phase II enzyme, NQO1, in human fetal lung cells. • AhR deficiency fails to abrogate omeprazole-mediated induction of NQO1. • Omeprazole increases phosphoNrf2 (S40) protein expression in human fetal lung cells. • Nrf2 knockdown abrogates the induction of NQO1 by omeprazole in human lung cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Parkin suppresses Drp1-independent mitochondrial division

The cycle of mitochondrial division and fusion disconnect and reconnect individual mitochondria in cells to remodel this energy-producing organelle. Although dynamin-related protein 1 (Drp1) plays a major role in mitochondrial division in cells, a reduced level of mitochondrial division still persists even in the absence of Drp1. It is unknown how much Drp1-mediated mitochondrial division accounts for the connectivity of mitochondria. The role of a Parkinson’s disease-associated protein—parkin, which biochemically and genetically interacts with Drp1—in mitochondrial connectivity also remains poorly understood. Here, we quantified the number and connectivity of mitochondria using mitochondria-targeted photoactivatable GFP in cells. We show that the loss of Drp1 increases the connectivity of mitochondria by 15-fold in mouse embryonic fibroblasts (MEFs). While a single loss of parkin does not affect the connectivity of mitochondria, the connectivity of mitochondria significantly decreased compared with a single loss of Drp1 when parkin was lost in the absence of Drp1. Furthermore, the loss of parkin decreased the frequency of depolarization of the mitochondrial inner membrane that is caused by increased mitochondrial connectivity in Drp1-knockout MEFs. Therefore, our data suggest that parkin negatively regulates Drp1-indendent mitochondrial division. -- Highlights: •A Drp1-mediated mechanism accounts for ∼95% of mitochondrial division. •Parkin controls the connectivity of mitochondria via a mechanism that is independent of Drp1. •In the absence of Drp1, connected mitochondria transiently depolarize. •The transient depolarization is independent of calcium signaling and uncoupling protein 2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

A novel alkaloid, evodiamine causes nuclear localization of cytochrome-c and induces apoptosis independent of p53 in human lung cancer cells

Lung cancer is the most frequently diagnosed malignancy that contributes to high proportion of deaths globally among patients who die due to cancer. Chemotherapy remains the common mode of treatment for lung cancer patients though with limited success. We assessed the biological effects and associated molecular changes of evodiamine, a plant alkaloid, on human lung cancer A549 and H1299 cells along with other epithelial cancer and normal lung SAEC cells. Our data showed that 20–40 μM evodiamine treatment for 24–48 h strongly (up to 73%, P < 0.001) reduced the growth and survival of these cancer cells. However, it also moderately inhibited growth and survival of SAEC cells. A strong inhibition (P < 0.001) was observed on clonogenicity of A549 cells. Further, evodiamine increased (4-fold) mitochondrial membrane depolarization with 6-fold increase in apoptosis and a slight increase in Bax/Bcl-2 ratio. It increased the cytochrome-c release from mitochondria into the cytosol as well as nucleus. Cytosolic cytochrome-c activated cascade of caspase-9 and caspase-3 intrinsic pathway, however, DR5 and caspase-8 extrinsic pathway was also activated which could be due to nuclear cytochrome-c. Pan-caspase inhibitor (z-VAD.fmk) partially reversed evodiamine induced apoptosis. An increase in p53 as well as its serine 15 phosphorylation was also observed. Pifithrin-α, a p53 inhibitor, slightly inhibited growth of A549 cells and under p53 inhibitory condition evodiamine-induced apoptosis could not be reversed. Together these findings suggest that evodiamine is a strong inducer of apoptosis in lung epithelial cancer cells independent of their p53 status and that could involve both intrinsic as well as extrinsic pathway of apoptosis. Thus evodiamine could be a potential anticancer agent against lung cancer. - Highlights: • Evodiamine, a novel plant alkaloid, relatively selectively inhibited growth and survival of human lung cancer cells. • Increased cancer cell apoptosis involving mitochondrial membrane depolarization. • Increased the cytochrome-c release from mitochondria into the cytosol as well as nucleus. • DR5 and caspase-8 extrinsic pathway was also activated in p53-independent manner. • Thus evodiamine could be a potential anticancer agent against lung cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Deltamethrin induced RIPK3-mediated caspase-independent non-apoptotic cell death in rat primary hepatocytes

Deltamethrin (DLM), a synthetic pyrethroid insecticide, is used all over the world for indoor and field pest management. In the present study, we investigated the elicited pathogenesis of DLM-induced hepatotoxicity in rat primary hepatocytes. DLM-induced cell death was accompanied with increased ROS generation, decreased mitochondrial membrane potential and G2/M arrest. Pre-treatment with N-acetyl cysteine/butylated hydroxyanisole/IM54 could partly rescue hepatocytes suggesting that ROS might play a role in DLM-induced toxicity. Interestingly, DLM treatment resulted in a caspase-independent but non-apoptotic cell death. Pre-treatment with pan-caspase inhibitor (ZVAD-FMK) could not rescue hepatocytes. Unaltered caspase-3 activity and absence of cleaved caspase-3 also corroborated our findings. Further, LDH release and Transmission electron microscopy (TEM) analysis demonstrated that DLM incites membrane disintegrity and necrotic damage. Immunochemical staining revealed an increased expression of inflammatory markers (TNFα, NFκB, iNOS, COX-2) following DLM treatment. Moreover, the enhanced RIPK3 expression in DLM treated groups and prominent rescue from cell death by GSK-872 indicated that DLM exposure could induce programmed necrosis in hepatocytes. The present study demonstrates that DLM could induce hepatotoxicity via non-apoptotic mode of cell death. - Highlights: • Deltamethrin (DLM) induces caspase-independent death in rat primary hepatocytes. • RIPK3 played a central role in DLM-mediated programmed necrosis in liver cells. • Reactive oxygen species played a role in DLM mediated hepatotoxity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Ropivacaine inhibits the migration of esophageal cancer cells via sodium-channel-independent but prenylation-dependent inhibition of Rac1/JNK/paxillin/FAK

Highlights: • Ropivacaine potently inhibits migration in esophageal cancer cells. • Ropivacaine inhibits migration via sodium channel-independent manner. • Ropivacaine decreases small GTPases activities via inhibiting prenylation. • Ropivacaine inhibits migration via suppressing Rac1/JNK/paxillin/FAK. The direct anti-proliferative and pro-apoptotic effects of local anesthetics have been well documented in various cancers. However, whether local anesthetics affect cancer metastasis and their underlying molecular mechanisms are not well understood. In this work, we show that ropivacaine at the clinically relevant concentration significantly inhibits esophageal cancer cell migration. Interestingly, ropivacaine at the same concentration does not display inhibitory effects on esophageal cancer cell growth and survival. We further demonstrate that ropivacaine significantly decreases activities of GTPases including RhoA, Rac1 and Ras, and inhibits prenylation in esophageal cancer cells. In addition, the inhibitory effects of ropivacaine on GTPases activities and migration are abolished in the presence of geranylgeraniol and farnesol, demonstrating that ropivacaine inhibits GTPases activities via prenylation inhibition. Finally, we demonstrate that ropivacaine-inhibited esophageal cancer cell inhibition occurs independently of sodium channel but via suppressing Rac1/JNK/paxillin/FAK pathway. Our work demonstrates the potent anti-migratory effect of ropivacaine in esophageal cancer by attenuating prenylation-dependent migratory signalling events. These findings provide significant insight into the potential mechanisms by which local anaesthetics may negatively affect metastasis.

60 APPLIED LIFE SCIENCES↗