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DOE OSTI2016

TH-EF-204-05: Application of Small-Field Treatment: The Promises and Pitfalls of SBRT

Joanna E. Cygler, Jan Seuntjens, J. Daniel Bourland, M. Saiful Huq, Josep Puxeu Vaque, Daniel Zucca Aparicio, Tatiana Krylova, Yuri Kirpichev, Eric Ford, Caridad Borras Stereotactic Radiation Therapy (SRT) utilizes small static and dynamic (IMRT) fields, to successfully treat malignant and benign diseases using techniques such as Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiation Therapy (SBRT). SRT is characterized by sharp dose gradients for individual fields and their resultant dose distributions. For appropriate targets, small field radiotherapy offers improved treatment quality by allowing better sparing of organs at risk while delivering the prescribed target dose. Specialized small field treatment delivery systems, such as robotic-controlled linear accelerators, gamma radiosurgery units, and dynamic arc linear accelerators may utilize rigid fixation, image guidance, and tumor tracking, to insure precise dose delivery to static or moving targets. However, in addition to great advantages, small field delivery techniques present special technical challenges for dose calibration due to unique geometries and small field sizes not covered by existing reference dosimetry protocols such as AAPM TG-51 or IAEA TRS 398. In recent years extensive research has been performed to understand small field dosimetry and measurement instrumentation. AAPM, IAEA and ICRU task groups are expected to provide soon recommendations on the dosimetry of small radiation fields. In this symposium we will: 1] discuss the physics, instrumentation, methodologies and challenges for small field radiation dose measurements; 2] review IAEA and ICRU recommendations on prescribing, recording and reporting of small field radiation therapy; 3] discuss selected clinical applications and technical aspects for specialized image-guided, small field, linear accelerator based treatment techniques such as IMRT and SBRT. Learning Objectives: To learn the physics of small fields in contrast to dosimetry of conventional fields To learn about detectors suitable for small fields To learn about the role of Monte Carlo simulations in determination of small field output factors To provide an overview of the IAEA small field dosimetry recommendations To provide an overview of the content of the ICRU report on Prescribing, Reporting and Recording of Small Field Radiation Therapy. To learn about special technical considerations in delivering IMRT and SBRT treatments To appreciate specific challenges of IMRT implementation J. Seuntjens, Natural Sciences and Engineering Research Council; Canadian Institutes of Health Research.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

TH-EF-204-06: Closing

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Reconstruction of implanted marker trajectories from cone-beam CT projection images using interdimensional correlation modeling

Purpose: Cone-beam CT (CBCT) is a widely used imaging modality for image-guided radiotherapy. Most vendors provide CBCT systems that are mounted on a linac gantry. Thus, CBCT can be used to estimate the actual 3-dimensional (3D) position of moving respiratory targets in the thoracic/abdominal region using 2D projection images. The authors have developed a method for estimating the 3D trajectory of respiratory-induced target motion from CBCT projection images using interdimensional correlation modeling. Methods: Because the superior–inferior (SI) motion of a target can be easily analyzed on projection images of a gantry-mounted CBCT system, the authors investigated the interdimensional correlation of the SI motion with left–right and anterior–posterior (AP) movements while the gantry is rotating. A simple linear model and a state-augmented model were implemented and applied to the interdimensional correlation analysis, and their performance was compared. The parameters of the interdimensional correlation models were determined by least-square estimation of the 2D error between the actual and estimated projected target position. The method was validated using 160 3D tumor trajectories from 46 thoracic/abdominal cancer patients obtained during CyberKnife treatment. The authors’ simulations assumed two application scenarios: (1) retrospective estimation for the purpose of moving tumor setup used just after volumetric matching with CBCT; and (2) on-the-fly estimation for the purpose of real-time target position estimation during gating or tracking delivery, either for full-rotation volumetric-modulated arc therapy (VMAT) in 60 s or a stationary six-field intensity-modulated radiation therapy (IMRT) with a beam delivery time of 20 s. Results: For the retrospective CBCT simulations, the mean 3D root-mean-square error (RMSE) for all 4893 trajectory segments was 0.41 mm (simple linear model) and 0.35 mm (state-augmented model). In the on-the-fly simulations, prior projections over more than 60° appear to be necessary for reliable estimations. The mean 3D RMSE during beam delivery after the simple linear model had established with a prior 90° projection data was 0.42 mm for VMAT and 0.45 mm for IMRT. Conclusions: The proposed method does not require any internal/external correlation or statistical modeling to estimate the target trajectory and can be used for both retrospective image-guided radiotherapy with CBCT projection images and real-time target position monitoring for respiratory gating or tracking.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Poster - 49: Assessment of Synchrony respiratory compensation error for CyberKnife liver treatment

The goal of this work is to quantify respiratory motion compensation errors for liver tumor patients treated by the CyberKnife system with Synchrony tracking, to identify patients with the smallest tracking errors and to eventually help coach patient’s breathing patterns to minimize dose delivery errors. The accuracy of CyberKnife Synchrony respiratory motion compensation was assessed for 37 patients treated for liver lesions by analyzing data from system logfiles. A predictive model is used to modulate the direction of individual beams during dose delivery based on the positions of internally implanted fiducials determined using an orthogonal x-ray imaging system and the current location of LED external markers. For each x-ray pair acquired, system logfiles report the prediction error, the difference between the measured and predicted fiducial positions, and the delivery error, which is an estimate of the statistical error in the model overcoming the latency between x-ray acquisition and robotic repositioning. The total error was calculated at the time of each x-ray pair, for the number of treatment fractions and the number of patients, giving the average respiratory motion compensation error in three dimensions. The 99{sup th} percentile for the total radial error is 3.85 mm, with the highest contribution of 2.79 mm in superior/inferior (S/I) direction. The absolute mean compensation error is 1.78 mm radially with a 1.27 mm contribution in the S/I direction. Regions of high total error may provide insight into features predicting groups of patients with larger or smaller total errors.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

Hydrogen Station Compression, Storage, and Dispensing Technical Status and Costs

The Independent Review Panel found that for a high-pressure tube-trailer delivery scenario, an 850-kg/d dispensing station resulted in the lowest cost of dispensed hydrogen based on the delivery technologies most likely to be available and thus represented the best approach toward achieving the U.S. Department of Energy’s 2020 dispensed hydrogen cost target for centrally produced hydrogen. The costs reviewed in this report include only those costs contributing to the selling price of hydrogen by the forecourt CSD portion of the hydrogen station and do not include the costs of production or delivery to the station.

08 HYDROGEN↗

DOE OSTI2022

Editorial: Nanotechnology for natural products

Humans around the globe have lived through an unprecedented time. The emergence and rapid spread of coronavirus disease 2019 (COVID-19) have resulted in the loss of millions of lives, and this number is still climbing every day and hour. As a consequence, there have been drastic changes over the past two years in how we live, communicate, and work, some of which may have changed forever: remote conferencing has become a new norm for businesses, schools, and academia; work-from-home and hybrid working is now more than just acceptable in many industries; most importantly, COVID-19 has raised global awareness of infectious diseases and pandemic responses to an exceptional level. Certainly, COVID-19 is not the only disease that is causing human suffering at this moment. Other highly contagious and lethal viruses, such as the human immunodeficiency virus (HIV), Ebola, and the recent addition to the list, Monkeypox, pose extraordinary challenges to modern civilizations. On the other hand, non-communicable diseases, such as heart disease, stroke, and cancer, are still claiming the majority of deaths on a global level (World Health Organization, 2020). Before the availability of synthetic drugs, civilizations worldwide relied on natural products extracted from the environment and various organisms for healthcare. Natural products and their derivatives continue to be critical components in the drug library available today. Indeed, almost a quarter of the new drugs approved by the US Food and Drug Administration (FDA) since 1981 are natural products, botanical mixtures, or their derivatives (Newman and Cragg, 2020). Recent developments in analytical characterization, genome mining, and engineering have further increased interest in drug discovery from the pool of natural products (Atanasov et al., 2021). This Research Topic celebrates a collection of studies at the intersection of natural product research and nanotechnological advances. As a successor and extension of the Research Topic in “Nanotechnology in Traditional Medicines and Natural Products” published last year (Zhang et al., 2021), the present collection focused more on recent developments in employing the synthesis and characterization of nanostructures for the delivery of functional natural products. Specifically, the use of carrier nanostructures to conjugate or encapsulate therapeutically active natural products with carrier nanostructures could enable their robust, targeted delivery tailored to either tackle a specific disease or unlock a drug administration pathway. Over the last decade, nanostructures such as liposomes (Pattni et al., 2015) and lipid nanoparticles (Hou et al., 2021) have been developed as versatile platforms for the inclusion and delivery of a wide range of therapeutical compounds; a significant advance in this aspect is the stabilization of mRNA strands for COVID-19 vaccination recently produced by Pfizer/BioNTech and Moderna (Tenchov et al., 2021). Such engineered nanomaterials are now widely used in the development of new drugs, while regulatory forces, such as the US FDA, remain cautious with the evaluation of each product on a case-by-case basis (Wang and Grainger, 2022). In this collection, Zeng et al. provided a timely review of natural products conjugated to and contained within nanomaterials for the ongoing COVID-19 pandemic. Natural products that are potentially useful in the mitigation of this disease, such as chloroquine and curcumin, supported in nanocarrier systems, have been discussed in detail. More broadly, Cheng et al. comprehensively reviewed the use of liposomes as a nanocarrier for natural products. This article provides a summary of natural product compounds and extracts used to form liposomal structures. Readers can further enjoy the practical aspects of these engineered drugs for the treatment of specific diseases as well as insights into future directions in this field.

peptides↗

DOE OSTI2015

Semiconductor-based photoelectrochemical water splitting at the limit of very wide depletion region

In semiconductor-based photoelectrochemical (PEC) water splitting, carrier separation and delivery largely relies on the depletion region formed at the semiconductor/water interface. As a Schottky junction device, the trade-off between photon collection and minority carrier delivery remains a persistent obstacle for maximizing the performance of a water splitting photoelectrode. Here, it is demonstrated that the PEC water splitting efficiency for an n-SrTiO 3 (n-STO) photoanode is improved very significantly despite its weak indirect band gap optical absorption (α < 10⁴ cm⁻¹), by widening the depletion region through engineering its doping density and profile. Graded doped n-SrTiO 3 photoanodes are fabricated with their bulk heavily doped with oxygen vacancies but their surface lightly doped over a tunable depth of a few hundred nanometers, through a simple low temperature re-oxidation technique. The graded doping profile widens the depletion region to over 500 nm, thus leading to very efficient charge carrier separation and high quantum efficiency (>70%) for the weak indirect transition. As a result, this simultaneous optimization of the light absorption, minority carrier (hole) delivery, and majority carrier (electron) transport by means of a graded doping architecture may be useful for other indirect band gap photocatalysts that suffer from a similar problem of weak optical absorption.

77 NANOSCIENCE AND NANOTECHNOLOGY↗

DOE OSTI2024

Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium

Abstract The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone‐related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16–1.70 for 17 years and older vs. 13–14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50–4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08–2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.

Shin, Aesun↗

DOE OSTI2019

An investigation of a novel reusable radiochromic sheet for 2D dose measurement

Purpose Radiochromic film remains a useful and versatile clinical dosimetry tool. Current film options are single use. Here, we introduce a novel prototype two‐dimensional (2D) radiochromic sheet, which optically clears naturally at room temperature after irradiation and can be reused. We evaluate the sheets for potential as a 2D dosimeter and as a radiochromic bolus with capability for dose measurement. Methods A novel derivative of reusable Presage ® was manufactured into thin sheets of 5 mm thickness. The sheets contained 2% cumin‐leucomalachitegreen‐diethylamine (LMG‐DEA) and plasticizer (up to 25% by weight). Irradiation experiments were performed to characterize the response to megavoltage radiation, including dose sensitivity, temporal decay rate, consistency of repeat irradiations, intra and inter‐sheet reproducibility, multi‐modality response (electrons and photons), and temperature sensitivity (22°C to 36°C). The local change in optical‐density (ΔOD), before and after radiation, was obtained with a flat‐bed film scanner and extracting the red channel. Repeat scanning enabled investigation of the temporal decay of ΔOD. Additional studies investigated clinical utility of the sheets through application to IMRT treatment plans (prostate and a TG119 commissioning plan), and a chest wall electron boost treatment. In the latter test, the sheet performed as a radiochromic bolus. Results The radiation induced OD change in the sheets was found to be proportional to dose and to exponentially decay to baseline in ~24 h (R2 = 0.9986). The sheet could be reused and had similar sensitivity (within 1% after the first irradiation) for at least eight irradiations. Importantly, no memory of previous irradiations was observed within measurement uncertainty. The consistency of dose response from photons (6 and 15 MV) and electrons (6–20 MeV) was found to be within calibration uncertainty (~1%). The dose sensitivity of the sheets had a temperature dependence of 0.0012 ΔOD/°C. For the short (1 min) single field IMRT QA verification, good agreement was observed between the Presage sheet and EBT film (gamma pass rate 97% at 3% 3 mm dose‐difference and distance‐to‐agreement tolerance, with a 10% threshold). For the longer (~13 min) TG‐119 9‐field IMRT verification the gamma agreement was lower at 93% pass rate at 5% 3 mm, 10% threshold, when compared with Eclipse. The lower rate is attributed to uncertainty arising from signal decay during irradiation and indicates a current limitation. For the electron cutout treatment, both Presage and EBT agreed well (within 2% RMS difference) but differed from the Eclipse treatment plan (~7% RMS difference) indicating some limitations to the Eclipse modeling in this case. The worst case estimates of uncertainty introduced by the signal decay for deliveries of 2, 5, and 10 min are 0.6%, 1.4%, and 2.8% respectively. Conclusions Reusable Presage sheets show promise for 2D dose measurement and as a radiochromic bolus for in vivo dose measurement. The current prototype is suitable for deliveries of length up to 5 min, where the uncertainty introduced by signal decay is anticipated to be ~1% (worst case 1.4%), or for longer deliveries where there is no temporal modulation (e.g. physical compensators, or open beams). Additionally, spatial resolution is limited by sheet thickness and scanner resolution, resulting in a practical resolution of 0.8 mm.

Collins, Cielle↗

DOE OSTI2022

Bayesian optimization to design a novel x-ray shaping device

In radiation therapy, x-ray dose must be precisely sculpted to the tumor, while simultaneously avoiding surrounding organs at risk. This requires modulation of x-ray intensity in space and/or time. Typically, this is achieved using a multi leaf collimator (MLC) - a complex mechatronic device comprising over one hundred individually powered tungsten ‘leaves’ that move in or out of the radiation field as required. Here, an all-electronic x-ray collimation concept with no moving parts is presented, termed “SPHINX”: Scanning Pencil-beam High-speed Intensity-modulated X-ray source. SPHINX utilizes a spatially distributed bremsstrahlung target and collimator array in conjunction with magnetic scanning of a high energy electron beam to generate a plurality of small x-ray “beamlets.” A simulation framework was developed in Topas Monte Carlo incorporating a phase space electron source, transport through user defined magnetic fields, bremsstrahlung x-ray production, transport through a SPHINX collimator, and dose in water. This framework was completely parametric, meaning a simulation could be built and run for any supplied geometric parameters. This functionality was coupled with Bayesian optimization to find the best parameter set based on an objective function which included terms to maximize dose rate for a user defined beamlet width while constraining inter-channel cross talk and electron contamination. Designs for beamlet widths of 5, 7, and 10 mm 2 were generated. Each optimization was run for 300 iterations and took approximately 40 h on a 24-core computer. For the optimized 7-mm model, a simulation of all beamlets in water was carried out including a linear scanning magnet calibration simulation. Finally, a back-of-envelope dose rate formalism was developed and used to estimate dose rate under various conditions. The optimized 5–, 7–, and 10-mm models had beamlet widths of 5.1 , 7.2 , and 10.1 mm 2 and dose rates of 3574, 6351, and 10 015 Gy/C, respectively. The reduction in dose rate for smaller beamlet widths is a result of both increased collimation and source occlusion. For the simulation of all beamlets in water, the scanning magnet calibration reduced the offset between the collimator channels and beam centroids from 2.9 ±1.9 mm to 0.01 ±0.03 mm. A slight reduction in dose rate of approximately 2% per degree of scanning angle was observed. Based on a back-of-envelope dose rate formalism, SPHINX in conjunction with next-generation linear accelerators has the potential to achieve substantially higher dose rates than conventional MLC-based delivery, with delivery of an intensity modulated 100 x 100 mm 2 field achievable in 0.9 to 10.6 s depending on the beamlet widths used. Bayesian optimization was coupled with Monte Carlo modeling to generate SPHINX geometries for various beamlet widths. A complete Monte Carlo simulation for one of these designs was developed, including electron beam transport of all beamlets through scanning magnets, x-ray production and collimation, and dose in water. These results demonstrate that SPHINX is a promising candidate for sculpting radiation dose with no moving parts, and has the potential to vastly improve both the speed and robustness of radiotherapy delivery. A multi-beam SPHINX system may be a candidate for delivering magavoltage FLASH RT in humans.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2013

Transseptal Guidewire Stabilization for Device Closure of a Large Pulmonary Arteriovenous Malformation

A 46-year-old man presenting with massive hemoptysis was found to have a large pulmonary arteriovenous malformation (PAVM) in the right lung. Closure of the PAVM with an Amplatzer-type duct occluder was hampered by inability to advance the device delivery sheath into the PAVM due to vessel tortuosity and inadequate guidewire support. Atrial septal puncture was performed and a femorofemoral arteriovenous guidewire loop through the right pulmonary artery, PAVM, and left atrium was created. Traction on both ends of the guidewire loop allowed advancement of the device delivery sheath into the PAVM and successful completion of the procedure. Transseptal guidewire stabilization can be a valuable option during device closure of large PAVMs when advancement, stability, or kinking of the device delivery sheath is an issue.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2016

Multiscale Modeling in the Clinic: Drug Design and Development

A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multi-scale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multi-scale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions to guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multi-scale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical techniques employed for multi-scale modeling approaches used in pharmacology and present several examples illustrating the current state-of-the-art regarding drug development for: Excitable Systems (Heart); Cancer (Metastasis and Differentiation); Cancer (Angiogenesis and Drug Targeting); Metabolic Disorders; and Inflammation and Sepsis. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multi-scale models.

Clancy, Colleen E.↗

DOE OSTI2020

3D RNA nanocage for encapsulation and shielding of hydrophobic biomolecules to improve the in vivo biodistribution

Ribonucleic acid (RNA) nanotechnology platforms have the potential of harboring therapeutics for in vivo delivery in disease treatment. However, the nonspecific interaction between the harbored hydrophobic drugs and cells or other components before reaching the diseased site has been an obstacle in drug delivery. In this work, we report an encapsulation strategy to prevent such nonspecific hydrophobic interactions in vitro and in vivo based on a self-assembled three-dimensional (3D) RNA nanocage. By placing an RNA three-way junction (3WJ) in the cavity of the nanocage, the conjugated hydrophobic molecules were specifically positioned within the nanocage, preventing their exposure to the biological environment. The assembly of the nanocages was characterized by native polyacrylamide gel electrophoresis (PAGE), atomic force microscopy (AFM), and cryogenic electron microscopy (cryo-EM) imaging. The stealth effect of the nanocage for hydrophobic molecules in vitro was evaluated by gel electrophoresis, flow cytometry, and confocal microscopy. The in vivo sheathing effect of the nanocage for hydrophobic molecules was assessed by biodistribution profiling in mice. The RNA nanocages with hydrophobic biomolecules underwent faster clearance in liver and spleen in comparison to their counterparts. Therefore, this encapsulation strategy holds promise for in vivo delivery of hydrophobic drugs for disease treatment.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Renewable energy integration and system operation challenge: control and optimization of millions of devices

The electric power infrastructure, originally designed and built on large-scale power plants, is evolving into a more resilient power generation and delivery system in which millions of smaller units of distributed energy generation resources units will be installed in sub-transmission and distribution networks. In order to control, manage and optimize the future grid, a hierarchical design is presented in this chapter which enables the distributed control on grid edge while inheriting the existing centralized control structure. This layered design of large-scale power system operation and control uses the following principle: reactive power control is treated as a primary control for voltage stability, and the real power control is primarily a grid-level control but can also be a supplementary control for voltage support in the case of insufficient reactive power control capacity. For the purpose of active control and operation at the distribution level, a recursive power network model is derived from nodal injection and branch power flow models. Based on the model, the proposed algorithms of hierarchical control, grid-edge inference and dynamic hosting allowance are developed and presented for multi-level controlled operation. And, a co-simulation architecture of integrated T&D system is presented to validate and demonstrate the feasibility and scalability of proposed algorithms.

Xu, Ying↗

DOE OSTI2022

Off-design performance of an organic Rankine-vapor compression cooling cycle using R1234ze(E)

In this study, a 264 kW th organic Rankine-vapor compression cycle (ORVC) was experimentally tested over a range of conditions to quantify the individual impact of off-design external conditions. The ORVC was designed to recover waste heat at 91 °C, reject heat to a liquid condenser stream at 30 °C, and produce chilled water at 7 °C. Here, the condenser heat rejection temperature was varied from 16.6 °C to 32.6 °C, the chilled water delivery temperature was varied between 2.1 °C and 13.1 °C, and the heat input temperature was varied from 91 °C to 120 °C. As the condenser heat rejection temperature decreased, the coefficient of performance (COP) of the ORVC improved from 0.558 at 30 °C to 0.682 at 16.6 °C, despite a reduction in compressor isentropic efficiency. Although the chilled water temperature variation had almost no impact on the organic Rankine cycle performance, the compressor efficiency decreased when the delivery temperature was below 7 °C. At the highest chilled water temperature, 13.1 °C, the COP of the ORVC was 0.643. Compressor stall was noted when the condenser heat rejection temperature was greater than 32.6 °C and the chilled water delivery temperature was below 2.1 °C. Increasing the driving heat source inlet temperature improved the COP of the ORVC and the thermal efficiency of the organic Rankine power cycle, while decreasing the efficiency of the compressor and the COP of vapor compression cycle. In addition, the integrated part load value of the system was determined through experimentation to be 0.682, which provides a realistic estimate of real-world performance.

30 DIRECT ENERGY CONVERSION↗

DOE OSTI2016

Development of exosome surface display technology in living human cells

Surface display technology is an emerging key player in presenting functional proteins for targeted drug delivery and therapy. Although a number of technologies exist, a desirable mammalian surface display system is lacking. Exosomes are extracellular vesicles that facilitate cell–cell communication and can be engineered as nano-shuttles for cell-specific delivery. In this study, we report the development of a novel exosome surface display technology by exploiting mammalian cell secreted nano-vesicles and their trans-membrane protein tetraspanins. By constructing a set of fluorescent reporters for both the inner and outer surface display on exosomes at two selected sites of tetraspanins, we demonstrated the successful exosomal display via gene transfection and monitoring fluorescence in vivo. We subsequently validated our system by demonstrating the expected intracellular partitioning of reporter protein into sub-cellular compartments and secretion of exosomes from human HEK293 cells. Lastly, we established the stable engineered cells to harness the ability of this robust system for continuous production, secretion, and uptake of displayed exosomes with minimal impact on human cell biology. In sum, our work paved the way for potential applications of exosome, including exosome tracking and imaging, targeted drug delivery, as well as exosome-mediated vaccine and therapy.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Optimized anion exchange column isolation of zirconium-89 (89Zr) from yttrium cyclotron target: Method development and implementation on an automated fluidic platform

Zirconium-89 (89Zr), produced by the (p,n) reaction from naturally monoisotopic yttrium (natY), is a promising positron emitting isotope for immunoPET imaging. Its long half-life of 78.4 h is sufficient for evaluating slow physiological processes. A prototype automated fluidic system, coupled to on-line and in-line detectors, has been constructed to facilitate development of new 89Zr purification methodologies. The highly reproducible reagent delivery platform and near-real time monitoring of column effluents allows for efficient method optimization. The separation of Zr from dissolved Y metal targets was evaluated using several anion exchange resins. Each resin was evaluated against its ability to quantitatively capture Zr from a load solution that is high in dissolved Y. The most appropriate anion exchange resin for this application was identified, and the separation method was optimized. The method is capable of a high Y decontamination factor (>105) and has been shown to separate Fe, an abundant contaminant in Y foils, from the 89Zr elution fraction. Finally, the performance of the method was evaluated using cyclotron bombarded Y foil targets. The separation method was shown to achieve >95% recovery of the 89Zr present in the foils. The 89Zr eluent, however, was in a chemical matrix not immediately conducive to labeling onto proteins. The main intent of this study was to develop a tandem column 89Zr purification process, wherein the anion exchange column method described here is the first separation in a dual-column purification process.

Zirconium-89, ImmunoPET, medical isotope, automati↗

DOE OSTI2021

Polarized $\mathrm{NORTIA}$ accumulation in response to pollen tube arrival at synergids promotes fertilization

Signal-mediated regulation of protein trafficking is an elegant mechanism for controlling the delivery of molecules to a precise location for critical signaling events that occur over short time frames. During plant reproduction, the FERONIA receptor complex is critical for intercellular communication that leads to gamete delivery; however, the impact of the FERONIA signal transduction cascade on protein trafficking in synergid cells remains unknown. Live imaging of pollen tube reception has revealed that a key outcome of FERONIA signaling is polar accumulation of the MLO protein NORTIA at the filiform apparatus in response to signals from an arriving pollen tube. Artificial delivery of NORTIA to the filiform apparatus is sufficient to bypass the FERONIA signaling pathway and to promote interspecific pollen tube reception. We propose that polar accumulation of NORTIA leads to the production of a secondary booster signal to ensure that pollen tubes burst to deliver the sperm cells for double fertilization.

59 BASIC BIOLOGICAL SCIENCES↗