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All sourcesNASA NTRSDOE OSTI
NASA NTRS2003

Advances in Thrust-Based Emergency Control of an Airplane

Engineers at NASA's Dryden Flight Research Center have received a patent on an emergency flight-control method implemented by a propulsion-controlled aircraft (PCA) system. Utilizing the preexisting auto-throttle and engine-pressure-ratio trim controls of the airplane, the PCA system provides pitch and roll control for landing an airplane safely without using aerodynamic control surfaces that have ceased to function because of a primary-flight-control-system failure. The installation of the PCA does not entail any changes in pre-existing engine hardware or software. [Aspects of the method and system at previous stages of development were reported in Thrust-Control System for Emergency Control of an Airplane (DRC-96-07), NASA Tech Briefs, Vol. 25, No. 3 (March 2001), page 68 and Emergency Landing Using Thrust Control and Shift of Weight (DRC-96-55), NASA Tech Briefs, Vol. 26, No. 5 (May 2002), page 58.]. Aircraft flight-control systems are designed with extensive redundancy to ensure low probabilities of failure. During recent years, however, several airplanes have exhibited major flight-control-system failures, leaving engine thrust as the last mode of flight control. In some of these emergency situations, engine thrusts were successfully modulated by the pilots to maintain flight paths or pitch angles, but in other situations, lateral control was also needed. In the majority of such control-system failures, crashes resulted and over 1,200 people died. The challenge lay in creating a means of sufficient degree of thrust-modulation control to safely fly and land a stricken airplane. A thrust-modulation control system designed for this purpose was flight-tested in a PCA an MD-11 airplane. The results of the flight test showed that without any operational control surfaces, a pilot can land a crippled airplane (U.S. Patent 5,330,131). The installation of the original PCA system entailed modifications not only of the flight-control computer (FCC) of the airplane but also of each engine-control computer. Inasmuch as engine-manufacturer warranties do not apply to modified engines, the challenge became one of creating a PCA system that does not entail modifications of the engine computers.

Creech, Gray↗
NASA NTRS2014

Re-Engineering the ISS Payload Operations Control Center During Increased Utilization and Critical Onboard Events

With an increase in the utilization and hours of payload operations being executed onboard the International Space Station (ISS), upgrading the NASA Marshall Space Flight Center (MSFC) Huntsville Operations Support Center (HOSC) ISS Payload Control Area (PCA) was essential to gaining efficiencies and assurance of current and future payload health and science return. PCA houses the Payload Operations Integration Center (POIC) responsible for the execution of all NASA payloads onboard the ISS. POIC Flight Controllers are responsible for the operation of voice, stowage, command, telemetry, video, power, thermal, and environmental control in support of ISS science experiments. The methodologies and execution of the PCA refurbishment were planned and performed within a four month period in order to assure uninterrupted operation of ISS payloads and minimal impacts to payload operations teams. To vacate the PCA, three additional HOSC control rooms were reconfigured to handle ISS realtime operations, Backup Control Center (BCC) to Mission Control in Houston, simulations, and testing functions. This involved coordination and cooperation from teams of ISS operations controllers, multiple engineering and design disciplines, management, and construction companies performing an array of activities simultaneously and in sync delivering a final product with no issues that impacted the schedule. For each console operator discipline, studies of Information Technology (IT) tools and equipment layouts, ergonomics, and lines of sight were performed. Infusing some of the latest IT into the project was an essential goal in ensuring future growth and success of the ISS payload science returns. Engineering evaluations led to a state of the art media wall implementation and more efficient ethernet cabling distribution providing the latest products and the best solution for the POIC. These engineering innovations led to cost savings for the project. Constraints involved in the management of the project included executing over 450 crew-hours of ISS real-time payload operations including a major onboard communications upgrade, SpaceX un-berth, a Soyuz launch, roll-out of ISS live video and interviews from the POIC, annual BCC certification and hurricane season, and ISS simulations and testing. Continuous ISS payload operations were possible during the PCA facility modifications with the reconfiguration of four control rooms and standup of two temporary control areas. Another major restriction to the project was an ongoing facility upgrade that included a NASA Headquarters mandated replacement of all electrical and mechanical systems and replacement of an external generator. These upgrades required a facility power outage during the PCA upgrades. The project also encompassed console layout designs and ordering, amenities selections and ordering, excessing of old equipment, moves, disposal of old IT equipment, camera installations, facility tour re-schedules, and contract justifications. These were just some of the tasks needed for a successful project.

Marsh, Angela L.↗
NASA NTRS2014

Re-Engineering the ISS Payload Operations Control Center During Increased Utilization and Critical Onboard Events

With an increase in utilization and hours of payload operations being executed onboard the International Space Station (ISS), upgrading the NASA Marshall Space Flight Center (MSFC) Huntsville Operations Support Center (HOSC) ISS Payload Control Area (PCA) was essential to gaining efficiencies and assurance of current and future payload health and science return. PCA houses the Payload Operations Integration Center (POIC) responsible for the execution of all NASA payloads onboard the ISS. POIC Flight Controllers are responsible for the operation of voice, stowage, command, telemetry, video, power, thermal, and environmental control in support of ISS science experiments. The methodologies and execution of the PCA refurbishment were planned and performed within a four-month period in order to assure uninterrupted operation of ISS payloads and minimal impacts to payload operations teams. To vacate the PCA, three additional HOSC control rooms were reconfigured to handle ISS real-time operations, Backup Control Center (BCC) to Mission Control in Houston, simulations, and testing functions. This involved coordination and cooperation from teams of ISS operations controllers, multiple engineering and design disciplines, management, and construction companies performing an array of activities simultaneously and in sync delivering a final product with no issues that impacted the schedule. For each console operator discipline, studies of Information Technology (IT) tools and equipment layouts, ergonomics, and lines of sight were performed. Infusing some of the latest IT into the project was an essential goal in ensuring future growth and success of the ISS payload science returns. Engineering evaluations led to a state of the art Video Wall implementation and more efficient ethernet cabling distribution providing the latest products and the best solution for the POIC. These engineering innovations led to cost savings for the project. Constraints involved in the management of the project included executing over 450 crew-hours of ISS real-time payload operations including a major onboard communications upgrade, SpaceX un-berth, a Soyuz launch, roll-out of ISS live video and interviews from the POIC, annual BCC certification and hurricane season, and ISS simulations and testing. Continuous ISS payload operations were possible during the PCA facility modifications with the reconfiguration of four control rooms and standup of two temporary control areas. Another major restriction to the project was an ongoing facility upgrade that included a NASA Headquarters mandated replacement of all electrical and mechanical systems and replacement of an external generator. These upgrades required a facility power outage during the PCA upgrades. The project also encompassed console layout designs and ordering, amenities selections and ordering, excessing of old equipment, moves, disposal of old IT equipment, camera installations, facility tour re-schedules, and contract justifications. These were just some of the tasks needed for a successful project. This paper describes the logistics and lessons learned in upgrading a control center capability in the middle of complex real-time operations. Combining the efficiencies of controller interaction and new technology infusion were prime drivers for this upgrade to handle the increased utilization of science research on ISS. The success of this project could not jeopardize the current operations while these facility upgrades occurred.

Dudley, Stephanie R. B.↗
NASA NTRSDate not supplied

Continuing Long-term Global SO 2 Data Record with JPSS OMPS Instruments

NASA’s long-term Earth Observing System (EOS) SO 2 climate data record (CDR) started with Aura/Ozone Monitoring Instrument (OMI, launched in 2004) and is now being continued with the SNPP/Ozone Mapping and Profiler Suite (OMPS, launched in 2011). Both OMI and SNPP/OMPS SO 2 CDRs are produced with the Goddard principal component analysis (PCA) spectral fitting algorithm. By inherently accounting for various instrumental factors, the PCA technique enables highly consistent retrievals between different instruments. In this presentation, we will provide an overview on our effort to further extend the EOS SO 2 CDR, by implementing the PCA SO 2 algorithm with multiple OMPS instruments flying on the Joint Polar Satellite System (JPSS) constellation, including NOAA-20 (launched in 2017) and NOAA-21 (launched in 2022). We will present results analyzing our new NOAA-20/OMPS PCA SO 2 EOS continuity product, to be publicly released in fall of 2023. We will show statistical analyses on the quality of NOAA-20 PCA SO 2 product, such as retrieval noise, biases over background areas, and long-term stability. We will employ a previously established top-down method to estimate SO2 emissions from selected large point sources, using NOAA-20 SO 2 retrievals and assimilated wind fields as input. The SO 2 emission estimates derived from NOAA-20 retrievals will be compared with those from OMI, SNPP/OMPS, and S5P/TROPOMI (TROPOspheric Monitoring Instrument). We will also demonstrate the application of a new machine learning technique that further reduces the noise of NOAA-20 SO 2 retrievals. Finally, we will present preliminary PCA SO 2 retrievals from recently launched satellite sensors, including NOAA-21/OMPS and NASA’s geostationary TEMPO (Tropospheric Emissions: Monitoring of Pollution) instrument.

SO2↗
DOE OSTI2016

Spatial Mapping of Pyocyanin in Pseudomonas Aeruginosa Bacterial Communities Using Surface Enhanced Raman Scattering

Surface enhanced Raman spectroscopy (SERS) imaging was used in conjunction with principal component analysis (PCA) for the in situ spatiotemporal mapping of the virulence factor pyocyanin in communities of the pathogenic bacterium Pseudomonas aeruginosa. The combination of SERS imaging and PCA analysis provides a robust method for the characterization of heterogeneous biological systems while circumventing issues associated with interference from sample autofluorescence and low reproducibility of SERS signals. The production of pyocyanin is found to depend both on the growth carbon source and on the specific strain of P. aeruginosa studied. A cystic fibrosis lung isolate strain of P. aeruginosa synthesizes and secretes pyocyanin when grown with glucose and glutamate, while the laboratory strain exhibits detectable production of pyocyanin only when grown with glutamate as the source of carbon. Pyocyanin production in the laboratory strain grown with glucose was below the limit of detection of SERS. In addition, the combination of SERS imaging and PCA can elucidate subtle differences in the molecular composition of biofilms. As a result, PCA loading plots from the clinical isolate exhibit features corresponding to vibrational bands of carbohydrates, which represent the mucoid biofilm matrix specific to that isolate, features that are not seen in the PCA loading plots of the laboratory strain.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

DEEPEN Global Standardized Categorical Exploration Datasets for Magmatic Plays

DEEPEN stands for DE-risking Exploration of geothermal Plays in magmatic ENvironments. As part of the development of the DEEPEN 3D play fairway analysis (PFA) methodology for magmatic plays (conventional hydrothermal, superhot EGS, and supercritical), weights needed to be developed for use in the weighted sum of the different favorability index models produced from geoscientific exploration datasets. This was done using two different approaches: one based on expert opinions, and one based on statistical learning. This GDR submission includes the datasets used to produce the statistical learning-based weights. While expert opinions allow us to include more nuanced information in the weights, expert opinions are subject to human bias. Data-centric or statistical approaches help to overcome these potential human biases by focusing on and drawing conclusions from the data alone. The drawback is that, to apply these types of approaches, a dataset is needed. Therefore, we attempted to build comprehensive standardized datasets mapping anomalies in each exploration dataset to each component of each play. This data was gathered through a literature review focused on magmatic hydrothermal plays along with well-characterized areas where superhot or supercritical conditions are thought to exist. Datasets were assembled for all three play types, but the hydrothermal dataset is the least complete due to its relatively low priority. For each known or assumed resource, the dataset states what anomaly in each exploration dataset is associated with each component of the system. The data is only a semi-quantitative, where values are either high, medium, or low, relative to background levels. In addition, the dataset has significant gaps, as not every possible exploration dataset has been collected and analyzed at every known or suspected geothermal resource area, in the context of all possible play types. The following training sites were used to assemble this dataset: - Conventional magmatic hydrothermal: Akutan (from AK PFA), Oregon Cascades PFA, Glass Buttes OR, Mauna Kea (from HI PFA), Lanai (from HI PFA), Mt St Helens Shear Zone (from WA PFA), Wind River Valley (From WA PFA), Mount Baker (from WA PFA). - Superhot EGS: Newberry (EGS demonstration project), Coso (EGS demonstration project), Geysers (EGS demonstration project), Eastern Snake River Plain (EGS demonstration project), Utah FORGE, Larderello, Kakkonda, Taupo Volcanic Zone, Acoculco, Krafla. - Supercritical: Coso, Geysers, Salton Sea, Larderello, Los Humeros, Taupo Volcanic Zone, Krafla, Reyjanes, Hengill. **Disclaimer: Treat the supercritical fluid anomalies with skepticism. They are based on assumptions due to the general lack of confirmed supercritical fluid encounters and samples at the sites included in this dataset, at the time of assembling the dataset. The main assumption was that the supercritical fluid in a given geothermal system has shared properties with the hydrothermal fluid, which may not be the case in reality. Once the datasets were assembled, principal component analysis (PCA) was applied to each. PCA is an unsupervised statistical learning technique, meaning that labels are not required on the data, that summarized the directions of variance in the data. This approach was chosen because our labels are not certain, i.e., we do not know with 100% confidence that superhot resources exist at all the assumed positive areas. We also do not have data for any known non-geothermal areas, meaning that it would be challenging to apply a supervised learning technique. In order to generate weights from the PCA, an analysis of the PCA loading values was conducted. PCA loading values represent how much a feature is contributing to each principal component, and therefore the overall variance in the data.

15 GEOTHERMAL ENERGY↗
DOE OSTI2019

Characteristics of missed prostate cancer lesions on 3T multiparametric-MRI in 518 patients: based on PI-RADSv2 and using whole-mount histopathology reference

Purpose: To determine the characteristics of missed prostate cancer (PCa) lesions on 3T multiparametric-MRI (mpMRI) based on PI-RADSv2 with whole-mount histopathology (WMHP) correlation. Materials and methods: This IRB-approved, HIPAA-compliant study, included 614 consecutive men with 3T mpMRI prior to prostatectomy at a single tertiary center between 12/2009 and 4/2017. Clinical, mpMRI, and pathologic features were obtained. PI-RADSv2-based MRI detected lesions were matched with previously finalized WMHP by a genitourinary (GU) radiologist and a GU pathologist. Patients with no mpMRI detected PCa lesion, but with at least one lesion ≥ 1 cm on WMHP, were reviewed retrospectively and assigned a PI-RADSv2 score. Tumor characteristics were compared between missed and detected lesions. Result: The final cohort included 518 patients with 1085 WMHP lesions. 51.9% (563/1085) of lesions were missed on 3T mpMRI. 71.4% (402/563), 21.7% (122/563), 4.4% (25/563), and 2.5% (14/563) of the missed lesions were Gleason scores (GS) 3 + 3, 3 + 4, 4 + 3, and 8 − 10, respectively. Missed PCa lesions had significantly lower proportion of GS ≥ 7 (p < 0.001) and smaller size for overall (p < 0.001) and index subcohorts (p < 0.001), as compared to detected lesions. 34.5% (194) of overall and 71.2% (79) index missed lesions were larger than 1 cm. In 13.7% (71/518) of patients without MR detected PCa, 149 lesions were detected on WMHP, with 70 (47%) lesions ≥ 1 cm. In retrospective review of these lesions, 42.9% (30), 18.6% (13), 21.5% (15), 10% (7), and 7% (5) were PI-RADSv2 1, 2, 3, 4, and 5, respectively. Conclusion: 3T mpMRI has an excellent per patients diagnostic performance for PCa and majority of missed lesions are clinically nonsignificant.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Transcatheter Arterial Embolization with a Mixture of Absolute Ethanol and Iodized Oil for Poorly Visualized Endophytic Renal Masses Prior to CT-Guided Percutaneous Cryoablation

PurposeTo retrospectively evaluate the feasibility of transcatheter arterial embolization (TAE) using a mixture of absolute ethanol and iodized oil to improve localization of endophytic renal masses on unenhanced computed tomography (CT) prior to CT-guided percutaneous cryoablation (PCA).Materials and MethodsOur institutional review board approved this retrospective study. From September 2011 to June 2015, 17 patients (mean age, 66.8 years) with stage T1a endophytic renal masses (mean diameter, 26.5 mm) underwent TAE using a mixture of absolute ethanol and iodized oil to improve visualization of small and endophytic renal masses on unenhanced CT prior to CT-guided PCA. TAE was considered successful that accumulated iodized oil depicted whole of the tumor edge on CT. PCA was considered successful when the iceball covered the entire tumor with over a 5 mm margin. Oncological and renal functional outcomes and complications were also evaluated.ResultsTAE was successfully performed in 16 of 17 endophytic tumors. The 16 tumors were performed under CT-guided PCA with their distinct visualization of localization and safe ablated margin. During the mean follow-up period of 15.4 ± 5.1 months, one patient developed local recurrence. Estimated glomerular filtration rate declined by 8 % with statistical significance (P = 0.01). There was no procedure-related significant complication.ConclusionTAE using a mixture of absolute ethanol and iodized oil to improve visualization of endophytic renal masses facilitated tumor localization on unenhanced CT, permitting depiction of the tumor edge as well as a safe margin for ablation during CT-guided PCA, with an acceptable decline in renal function.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

The E1 copper binding domain of full-length amyloid precursor protein mitigates copper-induced growth inhibition in brain metastatic prostate cancer DU145 cells

Highlights: • Copper levels are elevated in the tumour microenvironment. • APP mitigates copper-induced growth inhibition of DU145 prostate cancer (PCa) cells. • The APP intracellular domain is a prerequisite; soluble forms have no effect. • The E1 CuBD of APP is also a prerequisite. • APP copper binding potentially mitigates copper-induced PCa cell growth inhibition. - Abstract: Copper plays an important role in the aetiology and growth of tumours and levels of the metal are increased in the serum and tumour tissue of patients affected by a range of cancers including prostate cancer (PCa). The molecular mechanisms that enable cancer cells to proliferate in the presence of elevated copper levels are, therefore, of key importance in our understanding of tumour growth progression. In the current study, we have examined the role played by the amyloid precursor protein (APP) in mitigating copper-induced growth inhibition of the PCa cell line, DU145. A range of APP molecular constructs were stably over-expressed in DU145 cells and their effects on cell proliferation in the presence of copper were monitored. Our results show that endogenous APP expression was induced by sub-toxic copper concentrations in DU145 cells and over-expression of the wild-type protein was able to mitigate copper-induced growth inhibition via a mechanism involving the cytosolic and E1 copper binding domains of the full-length protein. APP likely represents one of a range of copper binding proteins that PCa cells employ in order to ensure efficient proliferation despite elevated concentrations of the metal within the tumour microenvironment. Targeting the expression of such proteins may contribute to therapeutic strategies for the treatment of cancers.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Silibinin attenuates ionizing radiation-induced pro-angiogenic response and EMT in prostate cancer cells

Graphical abstract: Potential model showing mechanism of silibinin-mediated attenuation of IR-induced angiogenic phenotype and EMT in tumor cells. Silibinin counters radiation induced invasive and migratory phenotype of cancer cells by down-regulating mitogenic pathways activated by IR, leading to inhibition of molecules including VEGF, iNOS, MMPs and N-cadherin. Silibinin also reverses IR mediated E-cadherin down-regulation, inhibiting EMT in tumor cells. Silibinin also radiosensitizes endothelial cells, reduces capillary tube formation by targeting various pro-angiogenic molecules. Further, silibinin may inhibit autocrine and paracrine signaling between tumor and endothelial cells by decreasing the levels of VEGF and other signaling molecules activated in response to IR. - Highlights: • Silibinin radiosensitizes endothelial cells. • Silibinin targets ionization radiation (IR)-induced EMT in PCa cells. • Silibinin is in phase II clinical trial in PCa patients, hence clinically relevant. - Abstract: Radiotherapy of is well established and frequently utilized in prostate cancer (PCa) patients. However, recurrence following therapy and distant metastases are commonly encountered problems. Previous studies underline that, in addition to its therapeutic effects, ionizing radiation (IR) increases the vascularity and invasiveness of surviving radioresistant cancer cells. This invasive phenotype of radioresistant cells is an upshot of IR-induced pro-survival and mitogenic signaling in cancer as well as endothelial cells. Here, we demonstrate that a plant flavonoid, silibinin can radiosensitize endothelial cells by inhibiting expression of pro-angiogenic factors. Combining silibinin with IR not only strongly down-regulated endothelial cell proliferation, clonogenicity and tube formation ability rather it strongly (p < 0.001) reduced migratory and invasive properties of PCa cells which were otherwise marginally affected by IR treatment alone. Most of the pro-angiogenic (VEGF, iNOS), migratory (MMP-2) and EMT promoting proteins (uPA, vimentin, N-cadherin) were up-regulated by IR in PCa cells. Interestingly, all of these invasive and EMT promoting actions of IR were markedly decreased by silibinin. Further, we found that potentiated effect was an end result of attenuation of IR-activated mitogenic and pro-survival signaling, including Akt, Erk1/2 and STAT-3, by silibinin.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Stroma-induced Jagged1 expression drives PC3 prostate cancer cell migration; disparate effects of RIP-generated proteolytic fragments on cell behaviour and Notch signaling

The Notch ligand Jagged1 is subject to regulated intramembrane proteolysis (RIP) which yields a soluble ectodomain (sJag) and a soluble Jagged1 intracellular domain (JICD). The full-length Jagged1 protein enhances prostate cancer (PCa) cell proliferation and is highly expressed in metastatic cells. However, little is known regarding the mechanisms by which Jagged1 or its RIP-generated fragments might promote PCa bone metastasis. In the current study we show that bone marrow stroma (BMS) induces Jagged1 expression in bone metastatic prostate cancer PC3 cells and that this enhanced expression is mechanistically linked to the promotion of cell migration. We also show that RIP-generated Jagged1 fragments exert disparate effects on PC3 cell behaviour and Notch signaling. In conclusion, the expression of both the full-length ligand and its RIP-generated fragments must be considered in tandem when attempting to regulate Jagged1 as a possible PCa therapy. - Highlights: • Bone marrow stroma induces Jagged1 expression in prostate cancer (PCa) PC3 cells. • This enhanced expression of full-length Jagged1 is required for PC3 cell migration. • Proteolytic fragments of Jagged1 exert disparate effects on PC3 cell behaviour. • Effects of fragments on cell behaviour do not correlate with Notch signaling. • Effects of Jagged1 and its fragments on PCa metastasis likely to be complex.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Coatomer subunit beta 2 (COPB2), identified by label-free quantitative proteomics, regulates cell proliferation and apoptosis in human prostate carcinoma cells

Highlights: • Our paper offered an available method to identified and confirm some differential expression of genes in prostate cancer. • Our paper provided us a common method to research the function of gene for prostate cancer. • Our paper helps us to identify a novel cancer related gene to explain for development of novel targeted drugs. Label-free quantitative proteomics has broad applications in the identification of differentially expressed proteins. Here, we applied this method to identify differentially expressed proteins (such as coatomer subunit beta 2 [COPB2]) and evaluated the functions and molecular mechanisms of these proteins in prostate cancer (PCA) cell proliferation. Proteins extracted from surgically resected PCA tissues and adjacent tissues of 3 patients were analyzed by label-free quantitative proteomics. The target protein was confirmed by bioinformatics and GEO dataset analyses. To investigate the role of the target protein in PCA, we used lentivirus-mediated small-interfering RNA (siRNA) to knockdown protein expression in the prostate carcinoma cell line, CWR22RV1 cells and assessed gene and protein expression by reverse transcription quantitative polymerase chain reaction and western blotting. CCK8 and colony formation assays were conducted to evaluate cell proliferation. Cell cycle distributions and apoptosis were assayed by flow cytometry. We selected the differentiation-related protein COPB2 as our target protein based on the results of label-free quantitative proteomics. High expression of COPB2 was found in PCA tissue and was related to poor overall survival based on a public dataset. Cell proliferation was significantly inhibited in COPB2-knockdown CWR22RV1 cells, as demonstrated by CCK8 and colony formation assays. Additionally, the apoptosis rate and percentage of cells in the G{sub 1} phase were increased in COPB2-knockdown cells compared with those in control cells. CDK2, CDK4, and cyclin D1 were downregulated, whereas p21 Waf1/Cip1 and p27 Kip1 were upregulated, affecting the cell cycle signaling pathway. COPB2 significantly promoted CWR22RV1 cell proliferation through the cell cycle signaling pathway. Thus, silencing of COPB2 may have therapeutic applications in PCA.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Activation of macrophages by a laccase-polymerized polyphenol is dependent on phosphorylation of Rac1

Various physiologically active effects of polymerized polyphenols have been reported. In this study, we synthesized a polymerized polyphenol (mL2a-pCA) by polymerizing caffeic acid using mutant Agaricus brasiliensis laccase and analyzed its physiological activity and mechanism of action. We found that mL2a-pCA induced morphological changes and the production of cytokines and chemokines in C3H/HeN mouse-derived resident peritoneal macrophages in vitro. The mechanisms of action of polymerized polyphenols on in vitro mouse resident peritoneal cells have not been characterized in detail previously. Herein, we report that the mL2a-pCA-induced production of interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) in C3H/HeN mouse-derived resident peritoneal cells was inhibited by treatment with the Rac1 inhibitor NSC23766 trihydrochloride. In addition, we found that mL2a-pCA activated the phosphorylation Rac1. Taken together, the results show that mL2a-pCA induced macrophage activation via Rac1 phosphorylation-dependent pathways.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902

Purpose: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). Methods and Materials: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥7 or clinical stage ≥T2 and GS ≥8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. Results: A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). Conclusions: NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

DNA-PKcs Expression Is a Predictor of Biochemical Recurrence After Permanent Iodine 125 Interstitial Brachytherapy for Prostate Cancer

Purpose: Predictive factors for biochemical recurrence (BCR) in localized prostate cancer (PCa) after brachytherapy are insufficient to date. Cellular radiosensitivity depends on DNA double-strand breaks, mainly repaired by the nonhomologous end-joining (NHEJ) system. We analyzed whether the expression of NHEJ proteins can predict BCR in patients treated by brachytherapy for localized PCa. Methods and Materials: From 983 PCa cases treated by brachytherapy between March 2000 and March 2012, 167 patients with available biopsy material suitable for in situ analysis were included in the study. The median follow-up time was 47 months. Twenty-nine patients experienced BCR. All slides were reviewed to reassess the Gleason score. Expression of the key NHEJ proteins DNA-PKcs, Ku70, and Ku80, and the proliferation marker Ki67, was studied by immunohistochemistry performed on tissue microarrays. Results: The Gleason scores after review (P=.06) tended to be associated with BCR when compared with the score initially reported (P=.74). Both the clinical stage (P=.02) and the pretreatment prostate-specific antigen level (P=.01) were associated with biochemical failure. Whereas the expression of Ku80 and Ki67 were not predictive of relapse, positive DNA-PKcs nuclear staining (P=.003) and higher Ku70 expression (P=.05) were associated with BCR. On multivariate analysis, among pretreatment variables, only DNA-PKcs (P=.03) and clinical stage (P=.02) remained predictive of recurrence. None of the patients without palpable PCa and negative DNA-PKcs expression experienced biochemical failure, compared with 32% of men with palpable and positive DNA-PKcs staining that recurred. Conclusions: Our results suggest that DNA-PKcs could be a predictive marker of BCR after brachytherapy, and this might be a useful tool for optimizing the choice of treatment in low-risk PCa patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Principal Component Analysis of azimuthal flow in intermediate-energy heavy-ion reactions

Principal Component Analysis (PCA) via Singular Value Decomposition (SVD) of large datasets is an adaptive exploratory method to uncover natural patterns underlying the data. Several recent applications of the PCA-SVD to event-by-event single-particle azimuthal angle distribution matrices in ultra-relativistic heavy-ion collisions at RHIC-LHC energies indicate that the sine and cosine functions chosen a priori in the traditional Fourier analysis are naturally the most optimal basis for azimuthal flow studies according to the data itself. We perform PCA-SVD analyses of mid-central Au+Au collisions at $E$ $beam$ / $A$ =1.23 GeV simulated using an isospin-dependent Boltzmann-Uehling-Uhlenbeck (IBUU) transport model to address the following two questions: (1) if the principal components of the covariance matrix of nucleon azimuthal angle distributions in heavy-ion reactions around 1 GeV/nucleon are naturally sine and/or cosine functions and (2) what if any advantages the PCA-SVD may have over the traditional flow analysis using the Fourier expansion for studying the EOS of dense nuclear matter. In conclusion, we find that (1) in none of our analyses the principal components come out naturally as sine and/or cosine functions, (2) while both the eigenvectors and eigenvalues of the covariance matrix are appreciably EOS dependent, the PCA-SVD has no apparent advantage over the traditional Fourier analysis for studying the EOS of dense nuclear matter using the azimuthal collective flow in heavy-ion collisions.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗
DOE OSTI2021

Development of platforms for functional characterization and production of phenazines using a multi-chassis approach via CRAGE

Phenazines (Phzs), a family of chemicals with a phenazine backbone, are secondary metabolites with diverse properties such as antibacterial, anti-fungal, or anticancer activity. The core derivatives of phenazine, phenazine-1-carboxylic acid (PCA) and phenazine-1,6-dicarboxylic acid (PDC), are themselves precursors for various other derivatives. Recent advances in genome mining tools have enabled researchers to identify many biosynthetic gene clusters (BGCs) that might produce novel Phzs. Here, to characterize the function of these BGCs efficiently, we performed modular construct assembly and subsequent multi-chassis heterologous expression using chassis-independent recombinase-assisted genome engineering (CRAGE). CRAGE allowed rapid integration of a PCA BGC into 23 diverse γ-proteobacteria species and allowed us to identify top PCA producers. We then used the top five chassis hosts to express four partially refactored PDC BGCs. A few of these platforms produced high levels of PDC. Specifically, Xenorhabdus doucetiae and Pseudomonas simiae produced PDC at a titer of 293 mg/L and 373 mg/L, respectively, in minimal media. These titers are significantly higher than those previously reported. Furthermore, selectivity toward PDC production over PCA production was improved by up to 9-fold. The results show that these strains are promising chassis for production of PCA, PDC, and their derivatives, as well as for function characterization of Phz BGCs identified via bioinformatics mining.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Non-invasive low charge electron beam time-of-arrival diagnostic using a plasmonics-enhanced photoconductive antenna

The use of a plasmonics-enhanced photoconductive antenna (PCA) optically gated by a near infrared (NIR) pulse enables non-invasive time-of-arrival measurements of a low charge electron beam with respect to the NIR reference, achieving picosecond resolution. The measured signal values show the expected scaling with the beam charge and distance from PCA to the beam axis, as the PCA samples the electric field of the passing electron beam. We operate the device with an NIR spot size much larger than the PCA active-area, resulting in a very simple optical setup and alignment procedure, making the plasmonics-enhanced PCA a preferred alternative to more complex timing diagnostics for applications requiring non-invasive picosecond or sub-picosecond timestamping.

43 PARTICLE ACCELERATORS↗