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At least 685 records · Page 38
All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

TU-F-BRF-02: MR-US Prostate Registration Using Patient-Specific Tissue Elasticity Property Prior for MR-Targeted, TRUS-Guided HDR Brachytherapy

Purpose: High-dose-rate (HDR) brachytherapy has become a popular treatment modality for prostate cancer. Conventional transrectal ultrasound (TRUS)-guided prostate HDR brachytherapy could benefit significantly from MR-targeted, TRUS-guided procedure where the tumor locations, acquired from the multiparametric MRI, are incorporated into the treatment planning. In order to enable this integration, we have developed a MR-TRUS registration with a patient-specific biomechanical elasticity prior. Methods: The proposed method used a biomechanical elasticity prior to guide the prostate volumetric B-spline deformation in the MRI and TRUS registration. The patient-specific biomechanical elasticity prior was generated using ultrasound elastography, where two 3D TRUS prostate images were acquired under different probe-induced pressures during the HDR procedure, which takes 2-4 minutes. These two 3D TRUS images were used to calculate the local displacement (elasticity map) of two prostate volumes. The B-spline transformation was calculated by minimizing the Euclidean distance between the normalized attribute vectors of the prostate surface landmarks on the MR and TRUS. This technique was evaluated through two studies: a prostate-phantom study and a pilot study with 5 patients undergoing prostate HDR treatment. The accuracy of our approach was assessed through the locations of several landmarks in the post-registration and TRUS images; our registration results were compared with the surface-based method. Results: For the phantom study, the mean landmark displacement of the proposed method was 1.29±0.11 mm. For the 5 patients, the mean landmark displacement of the surface-based method was 3.25±0.51 mm; our method, 1.71±0.25 mm. Therefore, our proposed method of prostate registration outperformed the surfaced-based registration significantly. Conclusion: We have developed a novel MR-TRUS prostate registration approach based on patient-specific biomechanical elasticity prior. Successful integration of multi-parametric MR and TRUS prostate images provides a prostate-cancer map for treatment planning, enables accurate dose planning and delivery, and potentially enhances prostate HDR treatment outcome.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

TH-A-BRF-10: Quantification of Subject-Specific Susceptibility-Related Geometric Distortion in Clinical Liver MRI for Radiation Therapy

Purpose: Subject-specific susceptibility-induced B0 inhomogeneity affects the geometric accuracy of MRI images, with potential impact on the accuracy of treatment planning and image guidance. This study quantifies individual distortions for patients with intrahepatic tumors. Methods: Liver MRI scans of 13 patients who were enrolled in an IRB approved study were acquired on a 3T scanner (Skyra, Siemens). Clinical contrast-enhanced images were acquired by a 3D Volume Interpolated Breath-Hold Examination (VIBE) sequence with TE/TR =1.65/4.3ms, voxel size = 2.5×2.5×3mm (axial sets) or 3.5×3.5×5mm (coronal sets), and frequency-encoding (FE) bandwidth of 440Hz/pixel. B0 inhomogeneity was evaluated by acquisition of dual gradient echoes (GRE) with TE1/TE2/TR =4.92/7.38/106ms, a voxel size of 3.5×3.5×3.75mm, a FE bandwidth of 290Hz/pixel and breath-hold. The phase difference maps from the two echoes were unwrapped using a quantitative MRI analysis software package (FSL, FMRIB, Oxford, UK). The resulting calculated B0 inhomogeneity maps (ΔB0 in Hz) were converted to voxel distortion maps in the FE direction (ΔX in mm) corresponding to the VIBE images. Results: Maximum susceptibility-induced distortions were observed in the liver dome near the diaphragm. Using results from coronal VIBE images in this study as examples, we observed clusters of voxels displaced close to or greater than ΔX=3.5mm (440 Hz in ΔB0) in the VIBE images of the liver in 3 patients, and greater than 2 mm but less than 3.5 mm in 12 patients. On average, approximately 14% of imaged liver voxels had distortions ΔX>±1mm (ΔB0>±125Hz) and 1% of the voxels had ΔX>±2mm (ΔB0>±250Hz). Conclusion: Although advanced MRI techniques, like VIBE, permit faster acquisitions allowing for breath-held examinations with limited motion-induced artifacts, this study suggests that localized distortions due to subject-specific susceptibility variations can occur and require additional advanced corrections based on measuring patient-specific B0 inhomogeneity maps. The authors would like to acknowledge funding support from NIH R01EB016079 and NIH/NCI RO1 CA132834.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

TH-C-BRD-05: Reducing Proton Beam Range Uncertainty with Patient-Specific CT HU to RSP Calibrations Based On Single-Detector Proton Radiography

Purpose: Beam range uncertainty in proton treatment comes primarily from converting the patient's X-ray CT (xCT) dataset to relative stopping power (RSP). Current practices use a single curve for this conversion, produced by a stoichiometric calibration based on tissue composition data for average, healthy, adult humans, but not for the individual in question. Proton radiographs produce water-equivalent path length (WEPL) maps, dependent on the RSP of tissues within the specific patient. This work investigates the use of such WEPL maps to optimize patient-specific calibration curves for reducing beam range uncertainty. Methods: The optimization procedure works on the principle of minimizing the difference between the known WEPL map, obtained from a proton radiograph, and a digitally-reconstructed WEPL map (DRWM) through an RSP dataset, by altering the calibration curve that is used to convert the xCT into an RSP dataset. DRWMs were produced with Plastimatch, an in-house developed software, and an optimization procedure was implemented in Matlab. Tests were made on a range of systems including simulated datasets with computed WEPL maps and phantoms (anthropomorphic and real biological tissue) with WEPL maps measured by single detector proton radiography. Results: For the simulated datasets, the optimizer showed excellent results. It was able to either completely eradicate or significantly reduce the root-mean-square-error (RMSE) in the WEPL for the homogeneous phantoms (to zero for individual materials or from 1.5% to 0.2% for the simultaneous optimization of multiple materials). For the heterogeneous phantom the RMSE was reduced from 1.9% to 0.3%. Conclusion: An optimization procedure has been designed to produce patient-specific calibration curves. Test results on a range of systems with different complexities and sizes have been promising for accurate beam range control in patients. This project was funded equally by the Engineering and Physical Sciences Research Council (UK) and Ion Beam Applications (Louvain-La-Neuve, Belgium)

07 ISOTOPE AND RADIATION SOURCES↗
DOE OSTI2014

Toward optimizing patient-specific IMRT QA techniques in the accurate detection of dosimetrically acceptable and unacceptable patient plans

Purpose: The authors investigated the performance of several patient-specific intensity-modulated radiation therapy (IMRT) quality assurance (QA) dosimeters in terms of their ability to correctly identify dosimetrically acceptable and unacceptable IMRT patient plans, as determined by an in-house-designed multiple ion chamber phantom used as the gold standard. A further goal was to examine optimal threshold criteria that were consistent and based on the same criteria among the various dosimeters. Methods: The authors used receiver operating characteristic (ROC) curves to determine the sensitivity and specificity of (1) a 2D diode array undergoing anterior irradiation with field-by-field evaluation, (2) a 2D diode array undergoing anterior irradiation with composite evaluation, (3) a 2D diode array using planned irradiation angles with composite evaluation, (4) a helical diode array, (5) radiographic film, and (6) an ion chamber. This was done with a variety of evaluation criteria for a set of 15 dosimetrically unacceptable and 9 acceptable clinical IMRT patient plans, where acceptability was defined on the basis of multiple ion chamber measurements using independent ion chambers and a phantom. The area under the curve (AUC) on the ROC curves was used to compare dosimeter performance across all thresholds. Optimal threshold values were obtained from the ROC curves while incorporating considerations for cost and prevalence of unacceptable plans. Results: Using common clinical acceptance thresholds, most devices performed very poorly in terms of identifying unacceptable plans. Grouping the detector performance based on AUC showed two significantly different groups. The ion chamber, radiographic film, helical diode array, and anterior-delivered composite 2D diode array were in the better-performing group, whereas the anterior-delivered field-by-field and planned gantry angle delivery using the 2D diode array performed less well. Additionally, based on the AUCs, there was no significant difference in the performance of any device between gamma criteria of 2%/2 mm, 3%/3 mm, and 5%/3 mm. Finally, optimal cutoffs (e.g., percent of pixels passing gamma) were determined for each device and while clinical practice commonly uses a threshold of 90% of pixels passing for most cases, these results showed variability in the optimal cutoff among devices. Conclusions: IMRT QA devices have differences in their ability to accurately detect dosimetrically acceptable and unacceptable plans. Field-by-field analysis with a MapCheck device and use of the MapCheck with a MapPhan phantom while delivering at planned rotational gantry angles resulted in a significantly poorer ability to accurately sort acceptable and unacceptable plans compared with the other techniques examined. Patient-specific IMRT QA techniques in general should be thoroughly evaluated for their ability to correctly differentiate acceptable and unacceptable plans. Additionally, optimal agreement thresholds should be identified and used as common clinical thresholds typically worked very poorly to identify unacceptable plans.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Dose reconstruction for real-time patient-specific dose estimation in CT

Purpose: Many recent computed tomography (CT) dose reduction approaches belong to one of three categories: statistical reconstruction algorithms, efficient x-ray detectors, and optimized CT acquisition schemes with precise control over the x-ray distribution. The latter category could greatly benefit from fast and accurate methods for dose estimation, which would enable real-time patient-specific protocol optimization. Methods: The authors present a new method for volumetrically reconstructing absorbed dose on a per-voxel basis, directly from the actual CT images. The authors’ specific implementation combines a distance-driven pencil-beam approach to model the first-order x-ray interactions with a set of Gaussian convolution kernels to model the higher-order x-ray interactions. The authors performed a number of 3D simulation experiments comparing the proposed method to a Monte Carlo based ground truth. Results: The authors’ results indicate that the proposed approach offers a good trade-off between accuracy and computational efficiency. The images show a good qualitative correspondence to Monte Carlo estimates. Preliminary quantitative results show errors below 10%, except in bone regions, where the authors see a bigger model mismatch. The computational complexity is similar to that of a low-resolution filtered-backprojection algorithm. Conclusions: The authors present a method for analytic dose reconstruction in CT, similar to the techniques used in radiation therapy planning with megavoltage energies. Future work will include refinements of the proposed method to improve the accuracy as well as a more extensive validation study. The proposed method is not intended to replace methods that track individual x-ray photons, but the authors expect that it may prove useful in applications where real-time patient-specific dose estimation is required.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-C-201-06: Utility of Quantitative 3D SPECT/CT Imaging in Patient Specific Internal Dosimetry of 153-Samarium with GATE Monte Carlo Package

Purpose: Patient-specific 3-dimensional (3D) internal dosimetry in targeted radionuclide therapy is essential for efficient treatment. Two major steps to achieve reliable results are: 1) generating quantitative 3D images of radionuclide distribution and attenuation coefficients and 2) using a reliable method for dose calculation based on activity and attenuation map. In this research, internal dosimetry for 153-Samarium (153-Sm) was done by SPECT-CT images coupled GATE Monte Carlo package for internal dosimetry. Methods: A 50 years old woman with bone metastases from breast cancer was prescribed 153-Sm treatment (Gamma: 103keV and beta: 0.81MeV). A SPECT/CT scan was performed with the Siemens Simbia-T scanner. SPECT and CT images were registered using default registration software. SPECT quantification was achieved by compensating for all image degrading factors including body attenuation, Compton scattering and collimator-detector response (CDR). Triple energy window method was used to estimate and eliminate the scattered photons. Iterative ordered-subsets expectation maximization (OSEM) with correction for attenuation and distance-dependent CDR was used for image reconstruction. Bilinear energy mapping is used to convert Hounsfield units in CT image to attenuation map. Organ borders were defined by the itk-SNAP toolkit segmentation on CT image. GATE was then used for internal dose calculation. The Specific Absorbed Fractions (SAFs) and S-values were reported as MIRD schema. Results: The results showed that the largest SAFs and S-values are in osseous organs as expected. S-value for lung is the highest after spine that can be important in 153-Sm therapy. Conclusion: We presented the utility of SPECT-CT images and Monte Carlo for patient-specific dosimetry as a reliable and accurate method. It has several advantages over template-based methods or simplified dose estimation methods. With advent of high speed computers, Monte Carlo can be used for treatment planning on a day to day basis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-E-J-151: Day-To-Day Variations in Fraction-Specific Motion Modeling Using Patient 4DCBCT Images

Purpose: The goal of this study is to quantify the interfraction reproducibility of patient-specific motion models derived from 4DCBCT acquired on the day of treatment of lung cancer stereotactic body radiotherapy (SBRT) patients. Methods: Motion models are derived from patient 4DCBCT images acquired daily over 3–5 fractions of treatment by 1) applying deformable image registration between each 4DCBCT image and a reference phase from that day, resulting in a set of displacement vector fields (DVFs), and 2) performing principal component analysis (PCA) on the DVFs to derive a motion model. The motion model from the first day of treatment is compared to motion models from each successive day of treatment to quantify variability in motion models generated from different days. Four SBRT patient datasets have been acquired thus far in this IRB approved study. Results: Fraction-specific motion models for each fraction and patient were derived and PCA eigenvectors and their associated eigenvalues are compared for each fraction. For the first patient dataset, the average root mean square error between the first two eigenvectors associated with the highest two eigenvalues, in four fractions was 0.1, while it was 0.25 between the last three PCA eigenvectors associated with the lowest three eigenvalues. It was found that the eigenvectors and eigenvalues of PCA motion models for each treatment fraction have variations and the first few eigenvectors are shown to be more stable across treatment fractions than others. Conclusion: Analysis of this dataset showed that the first two eigenvectors of the PCA patient-specific motion models derived from 4DCBCT were stable over the course of several treatment fractions. The third, fourth, and fifth eigenvectors had larger variations.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-E-T-114: Analysis of MLC Errors On Gamma Pass Rates for Patient-Specific and Conventional Phantoms

Purpose: To evaluate whether a 3D patient-specific phantom is better able to detect known MLC errors in a clinically delivered treatment plan than conventional phantoms. 3D printing may make fabrication of such phantoms feasible. Methods: Two types of MLC errors were introduced into a clinically delivered, non-coplanar IMRT, partial brain treatment plan. First, uniformly distributed random errors of up to 3mm, 2mm, and 1mm were introduced into the MLC positions for each field. Second, systematic MLC-bank position errors of 5mm, 3.5mm, and 2mm due to simulated effects of gantry and MLC sag were introduced. The original plan was recalculated with these errors on the original CT dataset as well as cylindrical and planar IMRT QA phantoms. The original dataset was considered to be a perfect 3D patient-specific phantom. The phantoms were considered to be ideal 3D dosimetry systems with no resolution limitations. Results: Passing rates for Gamma Index (3%/3mm and no dose threshold) were calculated on the 3D phantom, cylindrical phantom, and both on a composite and field-by-field basis for the planar phantom. Pass rates for 5mm systematic and 3mm random error were 86.0%, 89.6%, 98% and 98.3% respectively. For 3.5mm systematic and 2mm random error the pass rates were 94.7%, 96.2%, 99.2% and 99.2% respectively. For 2mm systematic error with 1mm random error the pass rates were 99.9%, 100%, 100% and 100% respectively. Conclusion: A 3D phantom with the patient anatomy is able to discern errors, both severe and subtle, that are not seen using conventional phantoms. Therefore, 3D phantoms may be beneficial for commissioning new treatment machines and modalities, patient-specific QA and end-to-end testing.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-E-T-760: Tolerance Design for Site-Specific Range in Proton Patient QA Process Using the Six Sigma Model

Purpose: To show how tolerance design and tolerancing approaches can be used to predict and improve the site-specific range in patient QA process in implementing the Six Sigma. Methods: In this study, patient QA plans were selected according to 6 site-treatment groups: head &neck (94 cases), spine (76 cases), lung (89 cases), liver (53 cases), pancreas (55 cases), and prostate (121 cases), treated between 2007 and 2013. We evaluated a model of the Six Sigma that determines allowable deviations in design parameters and process variables in patient-specific QA, where possible, tolerance may be loosened, then customized if it necessary to meet the functional requirements. A Six Sigma problem-solving methodology is known as DMAIC phases, which are used stand for: Define a problem or improvement opportunity, Measure process performance, Analyze the process to determine the root causes of poor performance, Improve the process by fixing root causes, Control the improved process to hold the gains. Results: The process capability for patient-specific range QA is 0.65 with only ±1 mm of tolerance criteria. Our results suggested the tolerance level of ±2–3 mm for prostate and liver cases and ±5 mm for lung cases. We found that customized tolerance between calculated and measured range reduce that patient QA plan failure and almost all sites had failure rates less than 1%. The average QA time also improved from 2 hr to less than 1 hr for all including planning and converting process, depth-dose measurement and evaluation. Conclusion: The objective of tolerance design is to achieve optimization beyond that obtained through QA process improvement and statistical analysis function detailing to implement a Six Sigma capable design.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

WE-D-BRA-05: Pseudo In Vivo Patient Dosimetry Using a 3D-Printed Patient-Specific Phantom

Purpose: To test the feasibility of using 3D-printed patient-specific phantoms for intensity-modulated radiation therapy (IMRT) quality assurance (QA). Methods: We created a patient-specific whole-head phantom using a 3D printer. The printer data file was created from high-resolution DICOM computed tomography (CT) images of 3-year old child treated at our institution for medulloblastoma. A custom-modified extruder system was used to create tissue-equivalent materials. For the printing process, the Hounsfield Units from the CT images were converted to proportional volumetric densities. A 5-field IMRT plan was created from the patient CT and delivered to the 3D- phantom. Dose was measured by an ion chamber placed through the eye. The ion chamber was placed at the posterior edge of the planning target volume in a high dose gradient region. CT scans of the patient and 3D-phantom were fused by using commercial treatment planning software (TPS). The patient’s plan was calculated on the phantom CT images. The ion chamber’s active volume was delineated in the TPS; dose per field and total dose were obtained. Measured and calculated doses were compared. Results: The 3D-phantom dimensions and tissue densities were in good agreement with the patient. However, because of a printing error, there was a large discrepancy in the density in the frontal cortex. The calculated and measured treatment plan doses were 1.74 Gy and 1.72 Gy, respectively. For individual fields, the absolute dose difference between measured and calculated values was on average 3.50%. Conclusion: This study demonstrated the feasibility of using 3D-printed patient-specific phantoms for IMRT QA. Such phantoms would be particularly advantageous for complex IMRT treatment plans featuring high dose gradients and/or for anatomical sites with high variation in tissue densities. Our preliminary findings are promising. We anticipate that, once the printing process is further refined, the agreement between measured and calculated doses will improve.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-I-12: Region-Specific Dictionary Learning for Low-Dose X-Ray CT Reconstruction

Purpose: Dictionary learning based method has attracted more and more attentions in low-dose CT due to the superior performance on suppressing noise and preserving structural details. Considering the structures and noise vary from region to region in one imaging object, we propose a region-specific dictionary learning method to improve the low-dose CT reconstruction. Methods: A set of normal-dose images was used for dictionary learning. Segmentations were performed on these images, so that the training patch sets corresponding to different regions can be extracted out. After that, region-specific dictionaries were learned from these training sets. For the low-dose CT reconstruction, a conventional reconstruction, such as filtered back-projection (FBP), was performed firstly, and then segmentation was followed to segment the image into different regions. Sparsity constraints of each region based on its dictionary were used as regularization terms. The regularization parameters were selected adaptively according to different regions. A low-dose human thorax dataset was used to evaluate the proposed method. The single dictionary based method was performed for comparison. Results: Since the lung region is very different from the other part of thorax, two dictionaries corresponding to lung region and the rest part of thorax respectively were learned to better express the structural details and avoid artifacts. With only one dictionary some artifact appeared in the body region caused by the spot atoms corresponding to the structures in the lung region. And also some structure in the lung regions cannot be recovered well by only one dictionary. The quantitative indices of the result by the proposed method were also improved a little compared to the single dictionary based method. Conclusion: Region-specific dictionary can make the dictionary more adaptive to different region characteristics, which is much desirable for enhancing the performance of dictionary learning based method.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-I-38: Patient Organ Specific Dose Assessment in Coronary CT Angiograph Using Voxellaized Volume Dose Index in Monte Carlo Simulation

Purpose: Clinical use of multi detector computed tomography(MDCT) in diagnosis of diseases due to high speed in data acquisition and high spatial resolution is significantly increased. Regarding to the high radiation dose in CT and necessity of patient specific radiation risk assessment, the adoption of new method in the calculation of organ dose is completely required and necessary. In this study by introducing a conversion factor, patient organ dose in thorax region based on CT image data using MC system was calculated. Methods: The geometry of x-ray tube, inherent filter, bow tie filter and collimator were designed using EGSnrc/BEAMnrc MC-system component modules according to GE-Light-speed 64-slices CT-scanner geometry. CT-scan image of patient thorax as a specific phantom was voxellised with 6.25mm3 in voxel and 64×64×20 matrix size. Dose to thorax organ include esophagus, lung, heart, breast, ribs, muscle, spine, spinal cord with imaging technical condition of prospectively-gated-coronary CT-Angiography(PGT) as a step and shoot method, were calculated. Irradiation of patient specific phantom was performed using a dedicated MC-code as DOSXYZnrc with PGT-irradiation model. The ratio of organ dose value calculated in MC-method to the volume CT dose index(CTDIvol) reported by CT-scanner machine according to PGT radiation technique has been introduced as conversion factor. Results: In PGT method, CTDIvol was 10.6mGy and Organ Dose/CTDIvol conversion factor for esophagus, lung, heart, breast, ribs, muscle, spine and spinal cord were obtained as; 0.96, 1.46, 1.2, 3.28. 6.68. 1.35, 3.41 and 0.93 respectively. Conclusion: The results showed while, underestimation of patient dose was found in dose calculation based on CTDIvol, also dose to breast is higher than the other studies. Therefore, the method in this study can be used to provide the actual patient organ dose in CT imaging based on CTDIvol in order to calculation of real effective dose(ED) based on organ dose. This work has been supported by the research chancellor of tehran university of medical sciences(tums), school of medicine, Tehran, Iran.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-T-300: Impact of Electron Density Modeling of ArcCHECK Cylindricaldiode Array On 3DVH Patient Specific QA Software Tool Analysis

Purpose: 3DVH software is a patient specific quality assurance tool which estimates the 3D dose to the patient specific geometry with the help of Planned Dose Perturbation algorithm. The purpose of this study is to evaluate the impact of HU value of ArcCHECK phantom entered in Eclipse TPS on 3D dose & DVH QA analysis. Methods: Manufacturer of ArcCHECK phantom provides CT data set of phantom & recommends considering it as a homogeneous phantom with electron density (1.19 gm/cc or 282 HU) close to PMMA. We performed this study on Eclipse TPS (V13, VMS) & trueBEAM STx VMS Linac & ArcCHECK phantom (SNC). Plans were generated for 6MV photon beam, 20cm×20cm field size at isocentre & SPD (Source to phantom distance) of 86.7 cm to deliver 100cGy at isocentre. 3DVH software requires patients DICOM data generated by TPS & plan delivered on ArcCHECK phantom. Plans were generated in TPS by assigning different HU values to phantom. We analyzed gamma index & the dose profile for all plans along vertical down direction of beam’s central axis for Entry, Exit & Isocentre dose. Results: The global gamma passing rate (2% & 2mm) for manufacturer recommended HU value 282 was 96.3%. Detector entry, Isocentre & detector exit Doses were 1.9048 (1.9270), 1.00(1.0199) & 0.5078(0.527) Gy for TPS (Measured) respectively.The global gamma passing rate for electron density 1.1302 gm/cc was 98.6%. Detector entry, Isocentre & detector exit Doses were 1.8714 (1.8873), 1.00(0.9988) & 0.5211(0.516) Gy for TPS (Measured) respectively. Conclusion: Electron density value assigned by manufacturer does not hold true for every user. Proper modeling of electron density of ArcCHECK in TPS is essential to avoid systematic error in dose calculation of patient specific QA.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-G-TeP1-09: Modality-Specific Dose Gradient Modeling for Prostate IMRT Using Spherical Distance Maps of PTV and Isodose Contours

Purpose: Overlapping volume histogram (OVH) and distance-to-target histogram (DTH) calculations rely on the assumption that dose gradients are symmetric with respect to primary target volume (PTV) expansion and minimum distance to PTV surface, respectively. It is desirable to lift this assumption and instead account for achievable modality-specific dose gradients (MSDG) for a given PTV shape. Methods: From a library of 96 prostate 7-beam IMRT plans, we computed spherical distance maps (SDMs) for PTVs and 3 iso-dose contours. Each SDM contains the minimum distances between plan isocenter and the object’s surface for a fixed set of azimuthal and polar angles. We performed principal component analysis (PCA)-based missing data recovery with PTV SDM as input and a single iso-dose contour SDM as output. Repeating this process for the set of iso-dose contours sparsely reconstructed the MSDG for a given PTV. DVH points were computed from the MSDG for bladder and rectum (OARs) as a natural way of casting patient-specific geometric information into modality-specific dose space (vs. OVH and DTH where data is purely geometric). For comparison, we implemented a cumulative (c)DTH-based prediction algorithm, and produced DVH for both OARs separately. We then computed linear regressions between each method and the DVH of the original patient plan for three different OAR DVH points. Results: R-squared for MSD-Gcomputed DVH vs. original plan DVH at V90%, V80% and V60% of max dose were 0.86, 0.83, and 0.78, for bladder and 0.36, 0.52, and 0.55 for rectum, respectively; R-squared for cDTH-based predicted DVH vs. original plan DVH were 0.67, 0.81, and 0.83, for bladder and 0.44, 0.50, and 0.51, for rectum, respectively. Conclusion: By simply modeling the MSDG about a given PTV, we are able to reproduce DVHs consistent with a validated cDTH-based DVH prediction. Regression analysis suggests MSDG could further improve predictions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Beta variant of concern (VOC) resists neutralization by major classes of antibodies from COVID-19 patients and vaccinated individuals. In this study, serum of Beta-infected patients revealed reduced cross-neutralization of wild-type virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of VOC-specific clonotypes and accommodation of mutations present in Beta and Omicron into a major antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with wild type–elicited antibodies, including a public VH1-58 clonotype that targets the RBD ridge. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift, with implications for design of next-generation vaccines and therapeutics.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Rnf and Fix Have Specific Roles during Aerobic Nitrogen Fixation in Azotobacter vinelandii

Biological nitrogen fixation requires large amounts of energy in the form of ATP and low potential electrons to overcome the high activation barrier for cleavage of the dinitrogen triple bond. The model aerobic nitrogen-fixing bacteria, Azotobacter vinelandii, generates low potential electrons in the form of reduced ferredoxin (Fd) and flavodoxin (Fld) using two distinct mechanisms via the enzyme complexes Rnf and Fix. Both Rnf and Fix are expressed during nitrogen fixation, but deleting either rnf1 or fix genes has little effect on diazotrophic growth. However, deleting both rnf1 and fix eliminates the ability to grow diazotrophically. Rnf and Fix both use NADH as a source of electrons, but overcoming the energetics of NADH's endergonic reduction of Fd/Fld is accomplished through different mechanisms. Rnf harnesses free energy from the chemiosmotic potential, whereas Fix uses electron bifurcation to effectively couple the endergonic reduction of Fd/Fld to the exergonic reduction of quinone. Different reaction stoichiometries and condition-specific differential gene expression indicate specific roles for the two reactions. This work's complementary physiological studies and thermodynamic modeling reveal how Rnf and Fix balance redox homeostasis in various conditions. Specifically, the Fix complex is required for efficient growth under low oxygen concentrations, while Rnf is presumed to maintain reduced Fd/Fld production for nitrogenase under standard conditions. This work provides a framework for understanding how the production of low potential electrons sustains robust nitrogen fixation in various conditions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Development and validation of broad-range qualitative and clade-specific quantitative molecular probes for assessing mercury methylation in the environment

Two genes, hgcA and hgcB, are essential for microbial mercury (Hg)-methylation. Detection and estimation of their abundance, in conjunction with Hg concentration, bioavailability and biogeochemistry is critical in determining potential hot spots of methylmercury (MeHg) generation in at-risk environments. We developed broad-range degenerate PCR primers spanning known hgcAB genes to determine the presence of both genes in diverse environments. These primers were tested against an extensive set of pure cultures with published genomes, including 13 Deltaproteobacteria, nine Firmicutes, and nine methanogenic Archaea. A distinct PCR product at the expected size was confirmed for all hgcAB+ strains tested via Sanger sequencing. Additionally, we developed clade-specific degenerate quantitative primers (qPCR) that targeted hgcA for each of the three dominant Hg-methylating clades. The clade-specific qPCR primers amplified hgcA from 64%, 88% and 86% of tested pure cultures of Deltaproteobacteria, Firmicutes and Archaea, respectively, and were highly specific for each clade. Amplification efficiencies and detection limits were quantified for each organism. Primer sensitivity varied among species based on sequence conservation. Finally, to begin to evaluate the utility of our primer sets in nature, we tested hgcA and hgcAB recovery from pure cultures spiked into sand and soil. These novel quantitative molecular tools designed in this study will allow for more accurate identification and quantification of the individual Hg-methylating groups of microorganisms in the environment. Here, the resulting data will be essential in developing accurate and robust predictive models of Hg-methylation potential, ideally integrating the geochemistry of Hg methylation to the microbiology and genetics of hgcAB.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Bacterial hemophilin homologs and their specific type eleven secretor proteins have conserved roles in heme capture and are diversifying as a family

Cellular life relies on enzymes that require metals, which must be acquired from extracellular sources. Bacteria utilize surface and secreted proteins to acquire such valuable nutrients from their environment. These include the cargo proteins of the type eleven secretion system (T11SS), which have been connected to host specificity, metal homeostasis, and nutritional immunity evasion. This Sec-dependent, Gram-negative secretion system is encoded by organisms throughout the phylum Proteobacteria, including human pathogens Neisseria meningitidis, Proteus mirabilis, Acinetobacter baumannii, and Haemophilus influenzae. Experimentally verified T11SS-dependent cargo include transferrin-binding protein B (TbpB), the hemophilin homologs heme receptor protein C (HrpC), hemophilin A (HphA), the immune evasion protein factor-H binding protein (fHbp), and the host symbiosis factor nematode intestinal localization protein C (NilC). Here, we examined the specificity of T11SS systems for their cognate cargo proteins using taxonomically distributed homolog pairs of T11SS and hemophilin cargo and explored the ligand binding ability of those hemophilin cargo homologs. In vivo expression in Escherichia coli of hemophilin homologs revealed that each is secreted in a specific manner by its cognate T11SS protein. Sequence analysis and structural modeling suggest that all hemophilin homologs share an N-terminal ligand-binding domain with the same topology as the ligand-binding domains of the Haemophilus haemolyticus heme binding protein (Hpl) and HphA. We term this signature feature of this group of proteins the hemophilin ligand-binding domain. Network analysis of hemophilin homologs revealed five subclusters and representatives from four of these showed variable heme-binding activities, which, combined with sequence-structure variation, suggests that hemophilins are diversifying in function.

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