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DOE OSTI2020

Technology Transfer Excellence Award NTXBio

While a scientist at Los Alamos National Laboratory, Dr. Alex Koglin developed two compounds to create a better vaccine for Tuberculosis (TB). In 2015, Dr. Koglin took an entrepreneurial leave of absence from the Laboratory to start NTXBio, LLC. His objective was to develop and commercialize a TB vaccine based on two compounds he created while a scientist at the Los Alamos. In 2018, a total of 1.5 million people died from TB. According to the World Health Organization TB is the leading infectious disease resulting in death worldwide. Approximately one-quarter of the world’s population is infected with mycobacterium tuberculosis, the bacteria that causes TB. Dr. Koglin non-exclusively licensed the two compounds from Los Alamos and began further development of the technology in collaboration with the Government of South Africa and universities to address the need for a vaccine to prevent TB. In their research and development of the compounds there was no evidence of cross resistance between other bacteria and the bacteria that causes TB. The compounds were tested in mouse models and demonstrated they can treat TB. Also, the tests have not shown any of the massive side effects that the current treatments for TB are showing. The company started production of the compounds using current manufacturing processes. Using these processes NTXBio could not produce the compounds at a reasonable price to be available for patients in third world countries. The company shifted to developing a new methodology “invitro synthetic biology” that can increase the production of these compounds and other vaccine molecules in a more affordable way. Dr. Koglin’s startup NTXBio is working to positively influence and secure the world vaccine supply by developing rapid on-demand production of the full spectrum of protein vaccines. Starting with the TB vaccine and advancing to common childhood vaccines, emergency and experimental vaccines such as those needed for COVID-19. NTXBio is capable of accelerated prototyping and manufacturing with increased purity and greater stability while reducing both cost and production time. The newly developed production methodology can be applied to not only the TB compounds licensed from Los Alamos, but also to their compounds that advance vaccine production for other diseases. Their technology produces vaccines fast enough to be fully deployable in areas without the need of specialized storage conditions and response times.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

SU-E-J-199: A Software Tool for Quality Assurance of Online Replanning with MR-Linac

Purpose: To develop a quality assurance software tool, ArtQA, capable of automatically checking radiation treatment plan parameters, verifying plan data transfer from treatment planning system (TPS) to record and verify (R&V) system, performing a secondary MU calculation considering the effect of magnetic field from MR-Linac, and verifying the delivery and plan consistency, for online replanning. Methods: ArtQA was developed by creating interfaces to TPS (e.g., Monaco, Elekta), R&V system (Mosaiq, Elekta), and secondary MU calculation system. The tool obtains plan parameters from the TPS via direct file reading, and retrieves plan data both transferred from TPS and recorded during the actual delivery in the R&V system database via open database connectivity and structured query language. By comparing beam/plan datasets in different systems, ArtQA detects and outputs discrepancies between TPS, R&V system and secondary MU calculation system, and delivery. To consider the effect of 1.5T transverse magnetic field from MR-Linac in the secondary MU calculation, a method based on modified Clarkson integration algorithm was developed and tested for a series of clinical situations. Results: ArtQA is capable of automatically checking plan integrity and logic consistency, detecting plan data transfer errors, performing secondary MU calculations with or without a transverse magnetic field, and verifying treatment delivery. The tool is efficient and effective for pre- and post-treatment QA checks of all available treatment parameters that may be impractical with the commonly-used visual inspection. Conclusion: The software tool ArtQA can be used for quick and automatic pre- and post-treatment QA check, eliminating human error associated with visual inspection. While this tool is developed for online replanning to be used on MR-Linac, where the QA needs to be performed rapidly as the patient is lying on the table waiting for the treatment, ArtQA can be used as a general QA tool in radiation oncology practice. This work is partially supported by Elekta Inc.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

SU-F-BRD-09: A Random Walk Model Algorithm for Proton Dose Calculation

Purpose: To develop a random walk model algorithm for calculating proton dose with balanced computation burden and accuracy. Methods: Random walk (RW) model is sometimes referred to as a density Monte Carlo (MC) simulation. In MC proton dose calculation, the use of Gaussian angular distribution of protons due to multiple Coulomb scatter (MCS) is convenient, but in RW the use of Gaussian angular distribution requires an extremely large computation and memory. Thus, our RW model adopts spatial distribution from the angular one to accelerate the computation and to decrease the memory usage. From the physics and comparison with the MC simulations, we have determined and analytically expressed those critical variables affecting the dose accuracy in our RW model. Results: Besides those variables such as MCS, stopping power, energy spectrum after energy absorption etc., which have been extensively discussed in literature, the following variables were found to be critical in our RW model: (1) inverse squared law that can significantly reduce the computation burden and memory, (2) non-Gaussian spatial distribution after MCS, and (3) the mean direction of scatters at each voxel. In comparison to MC results, taken as reference, for a water phantom irradiated by mono-energetic proton beams from 75 MeV to 221.28 MeV, the gamma test pass rate was 100% for the 2%/2mm/10% criterion. For a highly heterogeneous phantom consisting of water embedded by a 10 cm cortical bone and a 10 cm lung in the Bragg peak region of the proton beam, the gamma test pass rate was greater than 98% for the 3%/3mm/10% criterion. Conclusion: We have determined key variables in our RW model for proton dose calculation. Compared with commercial pencil beam algorithms, our RW model much improves the dose accuracy in heterogeneous regions, and is about 10 times faster than MC simulations.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Model 9975 O-Ring Fixture Long-Term Leak Performance (FY2022 Status Report)

Leak testing experiments to monitor the aging performance of Viton® GLT and GLT-S O-rings used in the model 9975 shipping package has been ongoing since 2004 at Savannah River National Laboratory. Seventy tests using mock-up 9975 primary containment vessels (PCVs) with GLT O-rings were assembled and heated to temperatures ranging from 200 to 450 °F. Due to material substitution, fourteen tests with GLT-S O-rings were initiated in 2008 and heated to temperatures ranging from 200 to 400 °F. The conditioning temperatures are elevated compared to the calculated maximum O-ring temperature in a 9975 package in storage, 158 °F, to accelerate aging and enable observations of O-ring failures in a reasonable time frame. The fixtures are leak tested periodically and all GLT O-ring fixtures aging at 350 °F or above have failed to maintain a leak-tight seal. Eight GLT O-ring fixtures aging at 300 °F have failed after 2.8 to 5.7 years at temperature while the remaining fixtures at 300 °F were retired from testing following more than five years without failure. There has been one GLT O-ring fixture which failed after 13.4 years aging at 200 °F. However, 20 other GLT O-rings aging at 200 °F have remained leak-tight for over 14 years and remain in test. No failures have yet been observed in GLT O-ring fixtures aging at 270 °F for 10.4 years. All GLT-S O-ring fixtures aging at 300 °F or above have failed their leak test. No failures have yet been observed in GLT-S O-ring fixtures aging at 250 °F for 12.5 years. This year, one GLT-S O-ring fixture failed after 12.4 years aging at 200 °F. Data from the O-ring fixtures are generally consistent with results from compression stress-relaxation testing, and provide confidence in the predictive models based on those results. However, uncertainty exists in extrapolating these elevated temperature results to the lower temperatures of interest for normal storage in K-Area Complex (KAC). Oxygen consumption testing, which includes results from temperatures near KAC normal storage temperatures, is ongoing to provide further confidence and corroborate these extrapolations. The collective data from these test efforts suggest the minimum O-ring service life at KAC normal storage conditions should be at least 34 years for GLT and GLT-S O-rings. Measurement of compression set in O-rings removed from failed fixtures, compared to that from KAC surveillance O-rings, indicate significant margin remains for O-rings still in service in 9975 packages in KAC. Aging and periodic leak testing will continue for the remaining 25 mock-up PCV fixtures.

36 MATERIALS SCIENCE↗

DOE OSTI2015

SU-E-J-36: Comparison of CBCT Image Quality for Manufacturer Default Imaging Modes

Purpose CBCT is being increasingly used in patient setup for radiotherapy. Often the manufacturer default scan modes are used for performing these CBCT scans with the assumption that they are the best options. To quantitatively assess the image quality of these scan modes, all of the scan modes were tested as well as options with the reconstruction algorithm. Methods A CatPhan 504 phantom was scanned on a TrueBeam Linear Accelerator using the manufacturer scan modes (FSRT Head, Head, Image Gently, Pelvis, Pelvis Obese, Spotlight, & Thorax). The Head mode scan was then reconstructed multiple times with all filter options (Smooth, Standard, Sharp, & Ultra Sharp) and all Ring Suppression options (Disabled, Weak, Medium, & Strong). An open source ImageJ tool was created for analyzing the CatPhan 504 images. Results The MTF curve was primarily dictated by the voxel size and the filter used in the reconstruction algorithm. The filters also impact the image noise. The CNR was worst for the Image Gently mode, followed by FSRT Head and Head. The sharper the filter, the worse the CNR. HU varied significantly between scan modes. Pelvis Obese had lower than expected HU values than most while the Image Gently mode had higher than expected HU values. If a therapist tried to use preset window and level settings, they would not show the desired tissue for some scan modes. Conclusion Knowing the image quality of the set scan modes, will enable users to better optimize their setup CBCT. Evaluation of the scan mode image quality could improve setup efficiency and lead to better treatment outcomes.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

SU-E-T-43: Analytical Model for Photon Peripheral Dose in Radiotherapy Treatments

Purpose: The higher survival rate of radiotherapy patients entails a growing concern on second cancers associated to peripheral doses. Currently, dosimetry of out-of field doses is still under development. Our group has developed a methodology to estimate neutron equivalent dose in organs (1,2). We aimed to propose a model to estimate out-of-field photon doses in isocentric treatments from basic clinical data. Methods: The proposed function models the dose as the sum of leakage and scatter terms. The latter is modeled as a virtual source at the collimator, which suffers from attenuation in air and tissue, corrected by the inverse-square-law. The model was parameterized using experimental measurements with TLD700 chips placed inside an anthropomorphic phantom (6–18MV) irradiated with conformal and modulated techniques in Elekta, Siemens and Varian linacs. This model provides photon dose at a point as a function of clinical parameters as prescription dose/UM, PTV volume, distance to the field edge, height of the MLC leaves and distance from the the MLC to the isocenter. Model was tested against independent measurements (TLD100) for a VMAT treatment on a Elekta. Dose to organs is modeled from dose to points along the head-to-feet axis of the organ of a “standard man” escalated by patient height. Results: Our semi-empirical model depends on 3 given parameters (leakage parameter can be individualized). A novelty of our model, over other models (e.g., PERIDOSE), arises from its applicability to any technique (independently of the number of MU needed to deliver a dose). Differences between predictions and measurements were < 0.005mSv/UM. Conclusion: We have proposed a unique model which successfully account for photon peripheral organ dose. This model can be applied in the day-to-day clinic as it only needs a few basic parameters which are readily accessible.1. Radiother. Oncol. 107:234–243, 2013. 2. Phys. Med. Biol. 57:6167–6191, 2012.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

WE-G-BRA-05: IROC Houston On-Site Audits and Parameters That Affect Performance

Purpose: To highlight the IROC Houston on-site dosimetry audit program, and to investigate the impact of clinical conditions on the frequency of errors/recommendations noted by IROC Houston. Methods: The results of IROC Houston on-site audits from 2000-present were abstracted and compared to clinical parameters, this included 409 institutions and 1020 linacs. In particular, we investigated the frequency of recommendations versus year, and the impact of repeat visits on the number of recommendations. We also investigated the impact on the number of recommendations of several clinical parameters: the number and age of the linacs, the linac/TPS combination, and the scope of the QA program. Results: The number of recommendations per institution (3.1 average) has shown decline between 2000 and present, although the number of recommendations per machine (0.89) has not changed. Previous IROC Houston site visits did not Result in fewer recommendations on a repeat visit, but IROC Houston tests have changed substantially during the last 15 years as radiotherapy technology has changed. There was no impact on the number of recommendations based on the number of machines at the institution or the age of a given machine. The fewest recommendations were observed for Varian-Eclipse combinations (0.71 recs/machine), while Elekta- Pinnacle combinations yielded the most (1.62 recs/machine). Finally, in the TG-142 era (post-2010), those institutions that had a QA recommendation (n=77) had significantly more other recommendations (1.83 per institution) than those that had no QA rec (n=12, 1.33 per institution). Conclusion: Establishing and maintaining a successful radiotherapy program is challenging and areas of improvement can routinely be identified. Clinical conditions such as linac-TPS combinations and the establishment of a good QA program impact the frequency of errors/deficiencies identified by IROC Houston during their on-site review process.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

Integrated data-driven and experimental approaches to accelerate lead optimization targeting SARS-CoV- 2 main protease

Identification of potential therapeutic candidates can be expedited by integrating computational modeling with domain aware machine learning (ML) approaches followed by experimental validation. Generative deep learning models have been recently developed that can generate thousands of new candidates, but their physiochemical properties are typically not optimized. Using our deep learning models and a scaffold as a starting point, we generated tens of thousands of compounds for SARS-CoV-2 M pro that preserve the core scaffold. Here we utilized and implemented several computational tools such as structural alert and toxicity analysis, high throughput virtual screening, ML-based 3D quantitative structure–activity relationships, multi-parameter optimization, and graph neural networks on libraries of generated candidates to predict biological activity and binding affinity a priori. From these collective computational results, eight promising candidates were identified and tested experimentally using Native Mass Spectrometry (MS) and FRET-based functional assays. Two compounds, with quinazoline-2-thiol and acetylpiperidine core moiety showed IC 50 values in the low micromolar range: 2.95±0.0017 µM and 3.41±0.0015 µM, respectively. The molecular dynamics simulations further highlight that binding of these compounds results in allosteric modulations in the chain B and the interface domains of the M pro . The key fragments from these top hits can be used as input for closed loop lead optimization in the integrated pipeline.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2012

Evaluation of the Impact of Thin Pours on Saltstone Properties

The proposed Saltstone Disposal Unit 6 (SDU6) is a larger structure than the SDU4 cells and larger than the disposal units (SDU2, SDU3, and SDU5) currently in use or under construction. The additional capacity provided by SDU6 is desired to reduce life cycle costs and support site accelerated closure goals. The larger size of the planned SDU6 could result in saltstone being placed in thinner lifts as the unit is filled. This study was performed to determine whether thinner layers of saltstone negatively impact the performance of the waste form. A larger number of cold joints could potentially result in increased drying, salt deposition, and surface oxidation. A matrix of samples was prepared to simulate thin pours ranging from 0.5 to 6 inches thick. Each sample was cured for at least 28 days prior to further characterization. Leachability results showed that there is no obvious impact of the number of grout layers on the Leachability Index values for Na and NO 3 . The concentrations of Cr, NO 2 , and C 2 O 4 were below detection limits for all of the leachates. No attempt was made to evaluate the oxidation of these samples since no measureable Cr was leached, although this would appear to indicate that Cr in the samples remained reduced for cold joints with surfaces exposed for approximately four days. The results of hydraulic conductivity measurements showed that the number of cold joints in the samples did not have a significant impact on the measured values for the vertical lift orientation (i.e., when the flow path is perpendicular to the cold joints). For the horizontal lift orientation (i.e., when the flow path is parallel to the cold joints), the number of cold joints in the samples also did not appear to have a significant impact on hydraulic conductivity. The measured hydraulic conductivity was faster when the flow path was parallel to the cold joints as compared to when the flow path was perpendicular to the cold joints. Percolation testing showed increased flow when the number of cold joints was increased. Compressive strength testing showed that the maximum load at the onset of cracking was reduced by approximately 26% for those samples that contained cold joints as compared to the monolithic samples. The number of cold joints in the sample had no significant impact on the maximum load prior to cracking. The porosity of the samples was not influenced by cold joints. This result was expected as the porosity is a material property affected by the properties of the components (premix and salt solution) and the water to premix ratio. Overall, the only obvious impact of cold joints in the samples was to significantly increase hydraulic conductivity in the direction parallel to the cold joints. An increasing number of cold joints (thin layers) in the simulated saltstone samples did not exacerbate this effect, nor did it have a negative impact on the Leachability Indices or porosity for surfaces exposed for approximately four days. The presence of a cold joint reduced the compressive strength of the material, although this impact was seen regardless of the number of cold joints in the sample.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

DOE OSTI2015

Design and Analysis of Muon Beam Stop Support Structures [Thesis]

The primary objective of this thesis is to design and analyze support structures to be used in the installation, test and final positioning of the MBS throughout the life of the Mu2e experiment. There several requirements for the MBS imposed by both the scope of the experiment and, other components within the DS bore. The functions of the MBS are: 1. To limit the induced rates in the Tracker, the Calorimeter and the Cosmic Ray Veto due to backsplash-and-secondary interactions, and 2. To reduce radiation levels external to the Detector solenoid. The structures used in supporting the MBS will also adhere to requirements imposed by its functions. These requirements are critical to the support structures and affect design decisions. Other requirements critical to the design are imposed by the weight, positional tolerance and assembly procedure of the MBS, and also, the magnetic field and vacuum dose rate of the DS bore. A detailed breakdown of how each requirement affects the structural design can be found in chapter 2. Chapter 3 describes the design of each support structure and its attachment to the MBS while chapter 4 describes the results from structural analysis of the support structures. Chapter 5 describes evaluation for the design through testing and calculations while the conclusion in chapter 6 reports the current status at the time of this thesis submission with a plan for future work to be completed until final design and installation.

43 PARTICLE ACCELERATORS↗

DOE OSTI2010

Reactive oxygen species on bone mineral density and mechanics in Cu,Zn superoxide dismutase (Sod1) knockout mice

Research highlights: {yields} Reactive oxygen species (ROS) are considered to be a factor in the onset of a number of age-associated conditions, including loss of BMD. {yields} Cu,Zn-superoxide dismutase (Sod1) deficient mice have increased ROS, reduced bone mineral density, decreased bending stiffness, and decreased strength compared to WT controls. {yields} Increased ROS caused by the deficiency of Sod1, may be responsible for the changes in BMD and bone mechanics and therefore represent an appropriate model for studying mechanisms of age-associated bone loss. -- Abstract: Reactive oxygen species (ROS) play a role in a number of degenerative conditions including osteoporosis. Mice deficient in Cu,Zn-superoxide dismutase (Sod1) (Sod1{sup -/-} mice) have elevated oxidative stress and decreased muscle mass and strength compared to wild-type mice (WT) and appear to have an accelerated muscular aging phenotype. Thus, Sod1{sup -/-} mice may be a good model for evaluating the effects of free radical generation on diseases associated with aging. In this experiment, we tested the hypothesis that the structural integrity of bone as measured by bending stiffness (EI; N/mm{sup 2}) and strength (MPa) is diminished in Sod1{sup -/-} compared to WT mice. Femurs were obtained from male and female WT and Sod1{sup -/-} mice at 8 months of age and three-point bending tests were used to determine bending stiffness and strength. Bones were also analyzed for bone mineral density (BMD; mg/cc) using micro-computed tomography. Femurs were approximately equal in length across all groups, and there were no significant differences in BMD or EI with respect to gender in either genotype. Although male and female mice demonstrated similar properties within each genotype, Sod1{sup -/-} mice exhibited lower BMD and EI of femurs from both males and females compared with gender matched WT mice. Strength of femurs was also lower in Sod1{sup -/-} mice compared to WT as well as between genders. These data indicate that increased oxidative stress, due to the deficiency of Sod1 is associated with decreased bone stiffness and strength and Sod1{sup -/-} mice may represent an appropriate model for studying disease processes in aging bone.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

IBEX: An open infrastructure software platform to facilitate collaborative work in radiomics

Purpose: Radiomics, which is the high-throughput extraction and analysis of quantitative image features, has been shown to have considerable potential to quantify the tumor phenotype. However, at present, a lack of software infrastructure has impeded the development of radiomics and its applications. Therefore, the authors developed the imaging biomarker explorer (IBEX), an open infrastructure software platform that flexibly supports common radiomics workflow tasks such as multimodality image data import and review, development of feature extraction algorithms, model validation, and consistent data sharing among multiple institutions. Methods: The IBEX software package was developed using the MATLAB and C/C++ programming languages. The software architecture deploys the modern model-view-controller, unit testing, and function handle programming concepts to isolate each quantitative imaging analysis task, to validate if their relevant data and algorithms are fit for use, and to plug in new modules. On one hand, IBEX is self-contained and ready to use: it has implemented common data importers, common image filters, and common feature extraction algorithms. On the other hand, IBEX provides an integrated development environment on top of MATLAB and C/C++, so users are not limited to its built-in functions. In the IBEX developer studio, users can plug in, debug, and test new algorithms, extending IBEX’s functionality. IBEX also supports quality assurance for data and feature algorithms: image data, regions of interest, and feature algorithm-related data can be reviewed, validated, and/or modified. More importantly, two key elements in collaborative workflows, the consistency of data sharing and the reproducibility of calculation result, are embedded in the IBEX workflow: image data, feature algorithms, and model validation including newly developed ones from different users can be easily and consistently shared so that results can be more easily reproduced between institutions. Results: Researchers with a variety of technical skill levels, including radiation oncologists, physicists, and computer scientists, have found the IBEX software to be intuitive, powerful, and easy to use. IBEX can be run at any computer with the windows operating system and 1GB RAM. The authors fully validated the implementation of all importers, preprocessing algorithms, and feature extraction algorithms. Windows version 1.0 beta of stand-alone IBEX and IBEX’s source code can be downloaded. Conclusions: The authors successfully implemented IBEX, an open infrastructure software platform that streamlines common radiomics workflow tasks. Its transparency, flexibility, and portability can greatly accelerate the pace of radiomics research and pave the way toward successful clinical translation.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

SU-G-TeP2-01: Can EPID Based Measurement Replace Traditional Daily Output QA On Megavoltage Linac?

Purpose: To investigate the long term stability and viability of using EPID-based daily output QA via in-house and vendor driven protocol, to replace conventional QA tools and improve QA efficiency. Methods: Two Varian TrueBeam machines (TB1&TB2) equipped with electronic portal imaging devices (EPID) were employed in this study. Both machines were calibrated per TG-51 and used clinically since Oct 2014. Daily output measurement for 6/15 MV beams were obtained using SunNuclear DailyQA3 device as part of morning QA. In addition, in-house protocol was implemented for EPID output measurement (10×10 cm fields, 100 MU, 100cm SID, output defined over an ROI of 2×2 cm around central axis). Moreover, the Varian Machine Performance Check (MPC) was used on both machines to measure machine output. The EPID and DailyQA3 based measurements of the relative machine output were compared and cross-correlated with monthly machine output as measured by an A12 Exradin 0.65cc Ion Chamber (IC) serving as ground truth. The results were correlated using Pearson test. Results: The correlations among DailyQA3, in-house EPID and Varian MPC output measurements, with the IC for 6/15 MV were similar for TB1 (0.83–0.95) and TB2 (0.55–0.67). The machine output for the 6/15MV beams on both machines showed a similar trend, namely an increase over time as indicated by all measurements, requiring a machine recalibration after 6 months. This drift is due to a known issue with pressurized monitor chamber which tends to leak over time. MPC failed occasionally but passed when repeated. Conclusion: The results indicate that the use of EPID for daily output measurements has the potential to become a viable and efficient tool for daily routine LINAC QA, thus eliminating weather (T,P) and human setup variability and increasing efficiency of the QA process.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2025

Diagnostic-free onboard battery health assessment

Diverse usage patterns induce complex and variable aging behaviors in lithiumion batteries, complicating accurate health diagnosis and prognosis. Separate diagnostic cycles are often used to untangle the battery’s current state of health from prior complex aging patterns. However, these same diagnostic cycles alter the battery’s degradation trajectory, are time-intensive, and cannot be practically performed in onboard applications. Here, in this work, we leverage portions of operational measurements in combination with an interpretable machine learning model to enable rapid, onboard battery health diagnostics and prognostics without offline diagnostic testing and the requirement of historical data. We integrate mechanistic constraints within an encoder-decoder architecture to extract electrode states in a physically interpretable latent space and enable improved reconstruction of the degradation path. The health diagnosis model framework can be flexibly applied across diverse application interests with slight fine-tuning.

battery aging reconstruction↗

DOE OSTI2016

WE-FG-BRA-12: Research Work of the Radio-Dynamic Treatment Mechanism

Purpose: The finite penetration depth of Laser light has limited clinical applications for PDT. This present work investigates the activation of photosensitizers using Cerenkov light emission from 45MV photon beams produced in an LA45 cancer therapy accelerator. We have named this new treatment technique Radio-Dynamic Therapy (RDT). Methods: Monte Carlo simulations were made on various Cerenkov emission energies and their spectroscopy in excited target areas in order to estimate their photosensitizer inner activation efficiency. The Cerenkov light excitation efficiency used in RDT has been theoretically compared with the exotic excitation efficiency of external Laser light used in PDT. In addition, laboratory tests showed the differences of the excitation efficiencies between a patented catalyst coenzyme added as a substrate, and then without the coenzyme. A specific probe of DMA (Singlet Oxygen fluorescent probe-9, 10-dimethylanthracene) was also used to detect singlet oxygen. Finally, we also compared our results with similar previous experimental work reported in the scientific literature. Results: Our Monte Carlo results showed that the Cerenkov light intensity induced with 45MV beams from an LA45 is 8 – 10 times the Cerenkov light intensity induced with 6MV beams from conventional accelerators. Furthermore, the patented catalyst coenzyme enhanced the excitation efficiency of photosensitizers by 3–6 times under different conditions. In clinical situations, the new RDT technique also showed favorable outcomes for early and late stages of specific cancers and it is also good at metastatic cancer treatment. Conclusion: Our results indicated that the process of using the Cerenkov light emission to excite photosensitizers from 45MV photons has a similar process and efficiency as the conventional laser in PDT. Comparing the advantages of RDT with a conventional PDT, the RDT may be developed into a potential treatment modality for a wider range of cancers stages as well as for other diseases.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2010

Mesenchymal stem cell-conditioned medium accelerates skin wound healing: An in vitro study of fibroblast and keratinocyte scratch assays

We have used in vitro scratch assays to examine the relative contribution of dermal fibroblasts and keratinocytes in the wound repair process and to test the influence of mesenchymal stem cell (MSC) secreted factors on both skin cell types. Scratch assays were established using single cell and co-cultures of L929 fibroblasts and HaCaT keratinocytes, with wound closure monitored via time-lapse microscopy. Both in serum supplemented and serum free conditions, wound closure was faster in L929 fibroblast than HaCaT keratinocyte scratch assays, and in co-culture the L929 fibroblasts lead the way in closing the scratches. MSC-CM generated under serum free conditions significantly enhanced the wound closure rate of both skin cell types separately and in co-culture, whereas conditioned medium from L929 or HaCaT cultures had no significant effect. This enhancement of wound closure in the presence of MSC-CM was due to accelerated cell migration rather than increased cell proliferation. A number of wound healing mediators were identified in MSC-CM, including TGF-{beta}1, the chemokines IL-6, IL-8, MCP-1 and RANTES, and collagen type I, fibronectin, SPARC and IGFBP-7. This study suggests that the trophic activity of MSC may play a role in skin wound closure by affecting both dermal fibroblast and keratinocyte migration, along with a contribution to the formation of extracellular matrix.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Cancer/testis antigen LDHC promotes proliferation and metastasis by activating the PI3K/Akt/GSK-3β-signaling pathway and the in lung adenocarcinoma

The cancer/testis antigen lactate dehydrogenase-C4 (LDHC) is a specific isoenzyme of the LDH family that regulates invasion and metastasis in some malignancies; however, little is known regarding its role in progression of lung adenocarcinoma (LUAD). Thus, we investigated LDHC expression by immunohistochemistry, and analyzed its clinical significance in 88 LUAD specimens. The role and molecular mechanisms subserving LDHC in cellular proliferation, migration, and invasion were explored both in vitro and in vivo. As a result, we found that high LDHC expression was significantly correlated with clinicopathological features of aggressive LUAD and a poor prognosis. Overexpression of LDHC induced LUAD cells to produce lactate and ATP, increased their metastatic and invasive potential—, and accelerated xenograft tumor growth. We further demonstrated that overexpression of LDHC affected the expression of cell proliferation-related proteins (cyclin D1 and c-Myc) and epithelial-mesenchymal transition (EMT)-related proteins (MMP-2, MMP-9, E-cadherin, Vimentin, Twist, Slug, and Snail) both in vitro and in vivo. Finally, excessive activation of LDHC enhanced the phosphorylation levels of AKT and GSK-3β, revealing activation of the PI3K/Akt/GSK-3β oncogenic-signaling pathways. Treatment with a PI3K inhibitor reversed the effects of LDHC overexpression by inhibiting cellular proliferation, migration, and invasion, with diminished levels of p-Akt and p-GSK3β. PI3K inhibition also reversed cell proliferation-related and EMT-related proteins in LDHC-overexpressing A549 cells. In conclusion, LDHC promotes proliferation, migration, invasion, and EMT in LUAD cells via activation of the PI3K/Akt/GSK-3β pathway.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Shotgun Immunoproteomic Approach for the Discovery of Linear B-Cell Epitopes in Biothreat Agents Francisella tularensis and Burkholderia pseudomallei

Peptide-based subunit vaccines are coming to the forefront of current vaccine approaches, with safety and cost-effective production among their top advantages. Peptide vaccine formulations consist of multiple synthetic linear epitopes that together trigger desired immune responses that can result in robust immune memory. The advantages of linear compared to conformational epitopes are their simple structure, ease of synthesis, and ability to stimulate immune responses by means that do not require complex 3D conformation. Prediction of linear epitopes through use of computational tools is fast and cost-effective, but typically of low accuracy, necessitating extensive experimentation to verify results. On the other hand, identification of linear epitopes through experimental screening has been an inefficient process that requires thorough characterization of previously identified full-length protein antigens, or laborious techniques involving genetic manipulation of organisms. In this study, we apply a newly developed generalizable screening method that enables efficient identification of B-cell epitopes in the proteomes of pathogenic bacteria. As a test case, we used this method to identify epitopes in the proteome of Francisella tularensis (Ft), a Select Agent with a well-characterized immunoproteome. Our screen identified many peptides that map to known antigens, including verified and predicted outer membrane proteins and extracellular proteins, validating the utility of this approach. We then used the method to identify seroreactive peptides in the less characterized immunoproteome of Select Agent Burkholderia pseudomallei (Bp). This screen revealed known Bp antigens as well as proteins that have not been previously identified as antigens. Although B-cell epitope prediction tools Bepipred 2.0 and iBCE-EL classified many of our seroreactive peptides as epitopes, they did not score them significantly higher than the non-reactive tryptic peptides in our study, nor did they assign higher scores to seroreactive peptides from known Ft or Bp antigens, highlighting the need for experimental data instead of relying on computational epitope predictions alone. The present workflow is easily adaptable to detecting peptide targets relevant to the immune systems of other mammalian species, including humans (depending upon the availability of convalescent sera from patients), and could aid in accelerating the discovery of B-cell epitopes and development of vaccines to counter emerging biological threats.

60 APPLIED LIFE SCIENCES↗