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At least 217 records · Page 12
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

Genetic and structural studies of RABL3 reveal an essential role in lymphoid development and function

The small GTPase RABL3 is an oncogene of unknown physiological function. Homozygous knockout alleles of mouse Rabl3 were embryonic lethal, but a viable hypomorphic allele (xiamen [xm]) causing in-frame deletion of four amino acids from the interswitch region resulted in profound defects in lymphopoiesis. Impaired lymphoid progenitor development led to deficiencies of B cells, T cells, and natural killer (NK) cells in Rabl3 xm/xm mice. T cells and NK cells exhibited impaired cytolytic activity, and mice infected with mouse cytomegalovirus (MCMV) displayed elevated titers in the spleen. Myeloid cells were normal in number and function. Further, biophysical and crystallographic studies demonstrated that RABL3 formed a homodimer in solution via interactions between the effector binding surfaces on each subunit; monomers adopted a typical small G protein fold. RABL3 xm displayed a large compensatory alteration in switch I, which adopted a β-strand configuration normally provided by the deleted interswitch residues, thereby permitting homodimer formation. Dysregulated effector binding due to conformational changes in the switch I–interswitch–switch II module likely underlies the xm phenotype. One such effector may be GPR89, putatively an ion channel or G protein-coupled receptor (GPCR). RABL3, but not RABL3 xm , strongly associated with and stabilized GPR89, and an N-ethyl-N-nitrosourea (ENU)-induced mutation (explorer) in Gpr89 phenocopied Rabl3 xm .

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Basis for the ICRP’s updated biokinetic model for systemic astatine

The International Commission on Radiological Protection (ICRP) recently updated its biokinetic models for workers in a series of reports called the OIR (occupational intakes of radionuclides) series. A new biokinetic model for astatine (At), the heaviest member of the halogen family, was adopted in OIR Part 5 (ICRP in press). Occupational intakes of radionuclides: Part 5). Furthermore, this paper provides an overview of available biokinetic data for At; describes the basis for the ICRP's updated model for At; and tabulates dose coefficients for intravenous injection of each of the two longest lived and most important At isotopes, 211 At and 210 At. At-211 (T 1/2 = 7.214 h) is a promising radionuclide for use in targeted α-particle therapy due to several favourable properties including its half-life and the absence of progeny that could deliver significant radiation doses outside the region of α-particle therapy. At-210 (T 1/2 = 8.1 h) is an impurity generated in the production of 211 At in a cyclotron and represents a potential radiation hazard via its long-lived progeny 210 Po (T 1/2 = 138 days). Tissue dose coefficients for injected 210 At and 211 At based on the updated model are shown to differ considerably from values based on the ICRP's previous model for At, particularly for the thyroid, stomach wall, salivary glands, lungs, spleen, and kidneys.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2021

A novel polypeptide vaccine and adjuvant formulation of EV71

ABSTRACT Hand foot and mouth disease (HFMD) is an infectious disease mainly caused by Enterovirus 71 (EV 71). However, the effective treatment is limited currently. The aim of this study was to investigate the activity of the vaccine including the EV71 polypeptides mixed with a novel adjuvant containing CpG oligodeoxynucleotides (CpG ODNs). After collecting mouse sera, we determined the antibody concentration in serum by enzyme-linked immunosorbent assays (ELISA). Then, CD19+CD27+ B cells in the spleen were analysed by flow cytometry. The assay revealed that a substantial increase in antibody titers was achieved. This indicates a high level of immunogenicity for peptide vaccine and the good stability of adjuvant, also suggests that the combination of vaccine and adjuvant can stimulate the production of high-level antibodies and CD19+CD27+ B lymphocytes in mice. Furthermore, the antibody could effectively identify EV71 inactivated virus. The results demonstrated that the autonomous construction of EV71 polypeptide vaccine had a good immunogenicity. Moreover, the peptide vaccine injection with a novel adjuvant, which is easy to prepare, could cause a high antibody level of EV71 and shown a good application prospect.

Liu, Zhiang↗
DOE OSTI2022

Complex genetics cause and constrain fungal persistence in different parts of the mammalian body

Determining how genetic polymorphisms enable certain fungi to persist in mammalian hosts can improve understanding of opportunistic fungal pathogenesis, a source of substantial human morbidity and mortality. We examined the genetic basis of fungal persistence in mice using a cross between a clinical isolate and the lab reference strain of the budding yeast Saccharomyces cerevisiae. Employing chromosomally encoded DNA barcodes, we tracked the relative abundances of 822 genotyped, haploid segregants in multiple organs over time and performed linkage mapping of their persistence in hosts. Detected loci showed a mix of general and antagonistically pleiotropic effects across organs. General loci showed similar effects across all organs, while antagonistically pleiotropic loci showed contrasting effects in the brain vs the kidneys, liver, and spleen. Persistence in an organ required both generally beneficial alleles and organ-appropriate pleiotropic alleles. This genetic architecture resulted in many segregants persisting in the brain or in nonbrain organs, but few segregants persisting in all organs. These results show complex combinations of genetic polymorphisms collectively cause and constrain fungal persistence in different parts of the mammalian body.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

MO-E-17A-03: Monte Carlo CT Dose Calculation: A Comparison Between Experiment and Simulation Using ARCHER-CT

Purpose: To compare the CT doses derived from the experiments and GPU-based Monte Carlo (MC) simulations, using a human cadaver and ATOM phantom. Methods: The cadaver of an 88-year old male and the ATOM phantom were scanned by a GE LightSpeed Pro 16 MDCT. For the cadaver study, the Thimble chambers (Model 10×5−0.6CT and 10×6−0.6CT) were used to measure the absorbed dose in different deep and superficial organs. Whole-body scans were first performed to construct a complete image database for MC simulations. Abdomen/pelvis helical scans were then conducted using 120/100 kVps, 300 mAs and a pitch factor of 1.375:1. For the ATOM phantom study, the OSL dosimeters were used and helical scans were performed using 120 kVp and x, y, z tube current modulation (TCM). For the MC simulations, sufficient particles were run in both cases such that the statistical errors of the results by ARCHER-CT were limited to 1%. Results: For the human cadaver scan, the doses to the stomach, liver, colon, left kidney, pancreas and urinary bladder were compared. The difference between experiments and simulations was within 19% for the 120 kVp and 25% for the 100 kVp. For the ATOM phantom scan, the doses to the lung, thyroid, esophagus, heart, stomach, liver, spleen, kidneys and thymus were compared. The difference was 39.2% for the esophagus, and within 16% for all other organs. Conclusion: In this study the experimental and simulated CT doses were compared. Their difference is primarily attributed to the systematic errors of the MC simulations, including the accuracy of the bowtie filter modeling, and the algorithm to generate voxelized phantom from DICOM images. The experimental error is considered small and may arise from the dosimeters. R01 grant (R01EB015478) from National Institute of Biomedical Imaging and Bioengineering.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

MO-E-17A-06: Organ Dose in Abdomen-Pelvis CT: Does TG 111 Equilibrium Dose Concept Better Accounts for KVp Dependence Than Conventional CTDI?

Purpose: In CT imaging, a desirable quality assurance (QA) dose quantity should account for the dose variability across scan parameters and scanner models. Recently, AAPM TG 111 proposed to use equilibrium dose-pitch product, in place of CT dose index (CTDI100), for scan modes involving table translation. The purpose of this work is to investigate whether this new concept better accounts for the kVp dependence of organ dose than the conventional CTDI concept. Methods: The adult reference female extended cardiac-torso (XCAT) phantom was used for this study. A Monte Carlo program developed and validated for a 128-slice CT system (Definition Flash, Siemens Healthcare) was used to simulate organ dose for abdomenpelvis scans at five tube voltages (70, 80, 100, 120, 140 kVp) with a pitch of 0.8 and a detector configuration of 2x64x0.6 mm. The same Monte Carlo program was used to simulate CTDI100 and equilibrium dose-pitch product. For both metrics, the central and peripheral values were used together with helical pitch to calculate a volume-weighted average, i.e., CTDIvol and (Deq)vol, respectively. Results: While other scan parameters were kept constant, organ dose depended strongly on kVp; the coefficient of variation (COV) across the five kVp values ranged between 70–75% for liver, spleen, stomach, pancreas, kidneys, colon, small intestine, bladder, and ovaries, all of which were inside the primary radiation beam. One-way analysis of variance (ANOVA) for the effect of kVp was highly significant (p=3e−30). When organ dose was normalized by CTDIvol, the COV across the five kVp values reduced to 7–16%. The effect of kVp was still highly significant (p=4e−4). When organ dose was normalized by (Deq)vol, the COV further reduced to 4−12%. The effect of kVp was borderline significant (p=0.04). Conclusion: In abdomen-pelvis CT, TG 111 equilibrium dose concept better accounts for kVp dependence than the conventional CTDI. This work is supported by a faculty startup fund from the Cleveland State University.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

TU-F-12A-04: Differential Radiation Avoidance of Functional Liver Regions Defined by 99mTc-Sulfur Colloid SPECT/CT with Proton Therapy

Purpose: Radiotherapy for hepatocellular carcinoma patients is conventionally planned without consideration of spatial heterogeneity in hepatic function, which may increase risk of radiation-induced liver disease. Pencil beam scanning (PBS) proton radiotherapy (pRT) plans were generated to differentially decrease dose to functional liver volumes (FLV) defined on [{sup 99m}Tc]sulfur colloid (SC) SPECT/CT images (functional avoidance plans) and compared against conventional pRT plans. Methods: Three HCC patients underwent SC SPECT/CT scans for pRT planning acquired 15 min post injection over 24 min. Images were reconstructed with OSEM following scatter, collimator, and exhale CT attenuation correction. Functional liver volumes (FLV) were defined by liver:spleen uptake ratio thresholds (43% to 90% maximum). Planning objectives to FLV were based on mean SC SPECT uptake ratio relative to GTV-subtracted liver and inversely scaled to mean liver dose of 20 Gy. PTV target coverage (V{sub 95}) was matched between conventional and functional avoidance plans. PBS pRT plans were optimized in RayStation for single field uniform dose (SFUD) and systematically perturbed to verify robustness to uncertainty in range, setup, and motion. Relative differences in FLV DVH and target dose heterogeneity (D{sub 2}-D{sub 98})/D50 were assessed. Results: For similar liver dose between functional avoidance and conventional PBS pRT plans (D{sub mean}≤5% difference, V{sub 18Gy}≤1% difference), dose to functional liver volumes were lower in avoidance plans but varied in magnitude across patients (FLV{sub 70%max} D{sub mean}≤26% difference, V{sub 18Gy}≤8% difference). Higher PTV dose heterogeneity in avoidance plans was associated with lower functional liver dose, particularly for the largest lesion [(D{sub 2}-D{sub 98})/D{sub 50}=13%, FLV{sub 90%max}=50% difference]. Conclusion: Differential avoidance of functional liver regions defined on sulfur colloid SPECT/CT is feasible with proton therapy. The magnitude of benefit appears to be patient specific and dependent on tumor location, size, and proximity to functional volumes. Further investigation in a larger cohort of patients may validate the clinical utility of functional avoidance planning of HCC radiotherapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-E-T-561: Monte Carlo-Based Organ Dose Reconstruction Using Pre-Contoured Human Model for Hodgkins Lymphoma Patients Treated by Cobalt-60 External Beam Therapy

Purpose: Organ doses for the Hodgkin’s lymphoma patients treated with cobalt-60 radiation were estimated using an anthropomorphic model and Monte Carlo modeling. Methods: A cobalt-60 treatment unit modeled in the BEAMnrc Monte Carlo code was used to produce phase space data. The Monte Carlo simulation was verified with percent depth dose measurement in water at various field sizes. Radiation transport through the lung blocks were modeled by adjusting the weights of phase space data. We imported a precontoured adult female hybrid model and generated a treatment plan. The adjusted phase space data and the human model were imported to the XVMC Monte Carlo code for dose calculation. The organ mean doses were estimated and dose volume histograms were plotted. Results: The percent depth dose agreement between measurement and calculation in water phantom was within 2% for all field sizes. The mean organ doses of heart, left breast, right breast, and spleen for the selected case were 44.3, 24.1, 14.6 and 3.4 Gy, respectively with the midline prescription dose of 40.0 Gy. Conclusion: Organ doses were estimated for the patient group whose threedimensional images are not available. This development may open the door to more accurate dose reconstruction and estimates of uncertainties in secondary cancer risk for Hodgkin’s lymphoma patients. This work was partially supported by the intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2015

MO-F-CAMPUS-I-05: Radiation Dosimetry of 99mTc-IDA-D-[c(RGDfK)]2, a SPECT Agent for Angiogenesis Imaging

Purpose: Tc-99m labeled IDA-D-[c(RGDfK){sub 2} ( {sup 99m}Tc-RGD) is a recently developed radiotracer for gamma camera or single photon emission computed tomography (SPECT) imaging and promising agent for the visualization of angiogenesis. In this study, we investigated the internal radiation dosimetry of {sup 99m}Tc-RGD in humans. Methods: Six normal controls (F:M=4:2; 68.3±3.2 years; 56.5±10.7 kg) were participated in this study. Simultaneous anterior and posterior scans of whole-body were performed using dual head gamma camera system. Before the emission scan, transmission scan was performed just before injection of {sup 99m}Tc-RGD using Co-57 flood source. After an intravenous injection of 388.7±29.3 MBq of {sup 99m}Tc-RGD, six serial emission scans were performed at 0, 1, 2, 4, 8 and 24 hours post-injection. The anterior and posterior images were geometrically averaged and attenuation correction was applied using transmission scan image. Regions of interest (ROIs) were drawn on liver, gallbladder, kidneys, urinary bladder, spleen, brain, and large intestine. Time activity curves were obtained from serial emission scan and ROIs. The number of disintegrations per unit activity administered (residence time) were calculated from the area under the curve of time activity curves and injected dose of each patient. Finally, the radiation dose for each organ and effective doses were obtained using OLINDA/EXM 1.1 software and residence time. Results: High radiation doses were reported on renal and biliary excretion tracks such as urinary bladder wall, upper large intestine, kidneys, liver and gallbladder wall and their doses were 19.15±6.84, 19.28±4.78, 15.67±0.90, 9.13±1.71 and 9.09±2.03 µGy/MBq, respectively. The effective dose and effective dose equivalent were 5.08±0.53 and 7.11±0.58 µSv/MBq, respectively. Conclusion: We evaluated the radiation dose of 99mTc-RGD, which has an acceptable effective radiation dose compare to the other Tc-99m labeled radio-tracers.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

A GPU-accelerated Monte Carlo dose calculation platform and its application toward validating an MRI-guided radiation therapy beam model

Purpose: The clinical commissioning of IMRT subject to a magnetic field is challenging. The purpose of this work is to develop a GPU-accelerated Monte Carlo dose calculation platform based on PENELOPE and then use the platform to validate a vendor-provided MRIdian head model toward quality assurance of clinical IMRT treatment plans subject to a 0.35 T magnetic field. Methods: PENELOPE was first translated from FORTRAN to C++ and the result was confirmed to produce equivalent results to the original code. The C++ code was then adapted to CUDA in a workflow optimized for GPU architecture. The original code was expanded to include voxelized transport with Woodcock tracking, faster electron/positron propagation in a magnetic field, and several features that make gPENELOPE highly user-friendly. Moreover, the vendor-provided MRIdian head model was incorporated into the code in an effort to apply gPENELOPE as both an accurate and rapid dose validation system. A set of experimental measurements were performed on the MRIdian system to examine the accuracy of both the head model and gPENELOPE. Ultimately, gPENELOPE was applied toward independent validation of patient doses calculated by MRIdian’s KMC. Results: An acceleration factor of 152 was achieved in comparison to the original single-thread FORTRAN implementation with the original accuracy being preserved. For 16 treatment plans including stomach (4), lung (2), liver (3), adrenal gland (2), pancreas (2), spleen(1), mediastinum (1), and breast (1), the MRIdian dose calculation engine agrees with gPENELOPE with a mean gamma passing rate of 99.1% ± 0.6% (2%/2 mm). Conclusions: A Monte Carlo simulation platform was developed based on a GPU- accelerated version of PENELOPE. This platform was used to validate that both the vendor-provided head model and fast Monte Carlo engine used by the MRIdian system are accurate in modeling radiation transport in a patient using 2%/2 mm gamma criteria. Future applications of this platform will include dose validation and accumulation, IMRT optimization, and dosimetry system modeling for next generation MR-IGRT systems.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TU-AB-BRA-01: Abdominal Synthetic CT Generation in Support of Liver SBRT Dose Calculation

Purpose: To demonstrate and validate a technique for generating MRI-derived synthetic CT volumes (MRCTs) in support of adaptive liver SBRT. Methods: Under IRB approval, ten hepatocellular carcinoma patients were scanned using a single MR sequence (T1 Dixon-VIBE), yielding inherently-registered water, fat, and T1-weighted images. Air-containing voxels were identified by intensity thresholding. The envelope of the anterior vertebral bodies was segmented from the fat image by fitting a shape model to vertebral body candidate voxels, then using level sets to expand the contour outward. Fuzzy-C-Means (FCM) was then used to classify each non-air voxel in the image as fat, water, bone, or marrow. Bone and marrow only were classified within the vertebral body envelope. The MRCT was created by integrating the product of the FCM class probability with the assigned class density for each voxel. The resulting MRCTs were deformably aligned with planning CTs and 2-ARC SBRT VMAT plans were optimized on the MRCT density maps. Fluence was copied onto the CT density grids and dose recalculated. Results: The MRCTs faithfully reproduced most of the features visible in the corresponding CT image volumes, with exceptions of ribs and posterior spinous processes. The liver, vertebral bodies, kidneys, spleen and cord all had median HU differences of less than 75 between MRCT and CT images. PTV D99% values had an average 0.2% difference (standard deviation: 0.46%) between calculations on MRCT and CT density grids. The maximum difference in dose to 0.1cc of the PTV was 0.25% (std:0.49%). OAR dose differences were similarly small (mean:0.03Gy, std:0.26Gy). The largest normal tissue complication percentage (NTCP) difference was 1.48% (mean:0.06%, std:0.54%). Conclusions: MRCTs from a single abdominal imaging sequence are promising for use in SBRT dose calculation. Future work will focus on extending models to better define bones in the upper abdomen. Supported by NIHR01EB016079 and NIH1L30CA199594-01.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TU-H-CAMPUS-IeP1-04: Combined Organ Dose for Digital Subtraction Angiography and Computed Tomography Using Monte Carlo Simulation

Purpose: The purpose of this study was to evaluate the combined organ dose of digital subtraction angiography (DSA) and computed tomography (CT) using a Monte Carlo (MC) simulation on the abdominal intervention. Methods: The organ doses for DSA and CT were obtained with MC simulation and actual measurements using fluorescent-glass dosimeters at 7 abdominal portions in an Alderson-Rando phantom. DSA was performed from three directions: posterior anterior (PA), right anterior oblique (RAO), and left anterior oblique (LAO). The organ dose with MC simulation was compared with actual radiation dose measurements. Calculations for the MC simulation were carried out with the GMctdospp (IMPS, Germany) software based on the EGSnrc MC code. Finally, the combined organ dose for DSA and CT was calculated from the MC simulation using the X-ray conditions of a patient with a diagnosis of hepatocellular carcinoma. Results: For DSA from the PA direction, the organ doses for the actual measurements and MC simulation were 2.2 and 2.4 mGy/100 mAs at the liver, respectively, and 3.0 and 3.1 mGy/100 mAs at the spinal cord, while for CT, the organ doses were 15.2 and 15.1 mGy/100 mAs at the liver, and 14.6 and 13.5 mGy/100 mAs at the spinal cord. The maximum difference in organ dose between the actual measurements and the MC simulation was 11.0% of the spleen at PA, 8.2% of the spinal cord at RAO, and 6.1% of left kidney at LAO with DSA and 9.3% of the stomach with CT. The combined organ dose (4 DSAs and 6 CT scans) with the use of actual patient conditions was found to be 197.4 mGy for the liver and 205.1 mGy for the spinal cord. Conclusion: Our method makes it possible to accurately assess the organ dose to patients for abdominal intervention with combined DSA and CT.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

WE-FG-BRA-05: Potential Clinical Benefit of LINAC Flattening-Filter-Free (FFF) Mode - Improvement of Treatment Therapeutic Ratio

Purpose: Ultrahigh dose-rate radiation at >40Gy/s has demonstrated astonishing normal-tissue sparing and tumor control in recent preclinical naive and tumor-bearing rodent studies when compared to the same radiation dose at a conventional dose-rate. The working mechanism of this fascinating dose-rate effect is currently under investigation. The aims of this work include investigating 1) whether LINAC FFF mode radiation at approximately 1Gy/s also has an improved therapeutic ratio compared to the same radiation dose at the conventional dose-rate of 0.05Gy/s, and 2) the dose-rate effect’s potential working mechanism by studying the expression of the P53 gene, linked to tumor suppression and cell regulation after radiation damage. Methods: We used mouse model C57BL/6J, the same as that used in the ultrahigh dose-rate studies, and exposed them to total body irradiation (TBI) using the Elekta Versa accelerator 10MV photons. Mice (N=20) were given a total dose of 12Gy in both the high dose-rate group (n=10) using the FFF-mode and the conventional dose-rate group (n=10) using the conventional does rate mode. The FFF-mode treatment setup consisted of a 15cm×15cm field size setting at 53.2cm SSD while the conventional-mode set-up consisted of a 10cm×10cm field size at 100SSD. Post-radiation, animals were monitored daily for survival analysis and signs of moribundity requiring euthanasia. In addition, mouse spleens were harvested for P53 analysis at different time points. Results: For 12Gy TBI, the 1.3Gy/s FFF-mode high dose-rate produced a statistically significant (p=0.02) improvement in mouse survival compared to the 0.05Gy/s conventional dose-rate. An initial P53 study at the time of death time-point indicates that high dose-rate radiation induced a stronger expression of P53 than conventional dose-rate radiation. Conclusion: Our pilot study indicates that the FFF-mode high dose-rate radiation, which has been used largely to improve clinical throughput, may provide the added clinical benefit of improving treatment therapeutic ratio. Animal Studies were performed within the LCCC Animal Studies Core Facility at the University of North Carolina at Chapel Hill. The LCCC Animal Studies Core is supported in part by an NCI Center Core Support Grant (CA16086) to the UNC Lineberger Comprehensive Cancer Center.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

WE-FG-BRA-10: Radiodosimetry of a Novel Alpha Particle Therapy Targeted to Uveal Melanoma: Absorbed Dose to Organs in Mice

Purpose: The melanocortin-1 receptor (MC1R) is expressed in 94% of uveal melanomas and is described as an ideal target for this untreatable disease. MC1RL is a high affinity MC1R specific peptidomimetic ligand that can serve as a scaffold for therapeutic conjugates such as alpha particle emitting isotopes. The purpose of this study was to assess normal tissue distribution and risk as a result of using the DOTA chelator conjugated to MC1RL to deliver {sup 225}Ac: MC1RL-DOTA-{sup 225}Ac. Methods: 17 non-tumor bearing BALB/c mice were intravenously injected with the novel MC1RL-DOTA-{sup 225}Ac radiopharmaceutical with an average initial administered activity of 2.5 µCi. After the injection, three groups of animals (6, 6, and 5 per group) were euthanized at 24, 48, and 96 hour time points. A total of 11 organs of interest were harvested at each time point including kidneys and liver. Since the emitted alpha particles from {sup 225}Ac and its daughter products are not easy to detect directly, the isomeric gamma spectra were measured instead in the tissue samples using a modified Atomlab™ Gamma Counter (Biodex Medical Systems, Inc) and converted using factors for gamma ray abundance per alpha decay. Dosimetry was performed using measured radioactivity distribution in organs and the generalized internal dosimetry schema of MIRD pamphlet #21. Results: Our calculations have shown that the maximum absorbed dose was delivered to the liver with a total of 47 cGy per 96 hour period. The average dose per kidney was calculated to be 21 cGy. Heart, brain, lung, spleen, skin doses ranged from 0.01 to 1 cGy over the same time period. All animals gained weight over the 110 day decay period and no organ damage was observed by pathology. Conclusion: Based on our results, the risk of using the MC1RL-DOTA-{sup 225}Ac compound is relatively small in terms of deterministic radiation effects. Funding Support: NIH/NCI P50CA168536-03 Skin SPORE; NIH/NCI Phase I SBIR Contract #HHSN261201500067C; Imaging and Technology Center of Excellence at Moffitt. Disclosures and Conflict of Interest: Collaboration with Modulation Therapeutics, Inc.(MTI) and has been partially funded by sub-contracts from MTI via collaboration on a NIH/NCI phase I SBIR contract.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-AB-BRA-07: PENELOPE-Based GPU-Accelerated Dose Calculation System Applied to MRI-Guided Radiation Therapy

Purpose: The clinical commissioning of IMRT subject to a magnetic field is challenging. The purpose of this work is to develop a GPU-accelerated Monte Carlo dose calculation platform based on PENELOPE and then use the platform to validate a vendor-provided MRIdian head model toward quality assurance of clinical IMRT treatment plans subject to a 0.35 T magnetic field. Methods: We first translated PENELOPE from FORTRAN to C++ and validated that the translation produced equivalent results. Then we adapted the C++ code to CUDA in a workflow optimized for GPU architecture. We expanded upon the original code to include voxelized transport boosted by Woodcock tracking, faster electron/positron propagation in a magnetic field, and several features that make gPENELOPE highly user-friendly. Moreover, we incorporated the vendor-provided MRIdian head model into the code. We performed a set of experimental measurements on MRIdian to examine the accuracy of both the head model and gPENELOPE, and then applied gPENELOPE toward independent validation of patient doses calculated by MRIdian’s KMC. Results: We achieve an average acceleration factor of 152 compared to the original single-thread FORTRAN implementation with the original accuracy preserved. For 16 treatment plans including stomach (4), lung (2), liver (3), adrenal gland (2), pancreas (2), spleen (1), mediastinum (1) and breast (1), the MRIdian dose calculation engine agrees with gPENELOPE with a mean gamma passing rate of 99.1% ± 0.6% (2%/2 mm). Conclusions: We developed a Monte Carlo simulation platform based on a GPU-accelerated version of PENELOPE. We validated that both the vendor provided head model and fast Monte Carlo engine used by the MRIdian system are accurate in modeling radiation transport in a patient using 2%/2 mm gamma criteria. Future applications of this platform will include dose validation and accumulation, IMRT optimization, and dosimetry system modeling for next generation MR-IGRT systems.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-CD-206-08: An Anthropopathic Deformable Phantom for Geometric and Dose Accumulation Accuracy Validation of Deformable Image Registration

Purpose: To design and construct a three-dimensional (3D) anthropopathic abdominal phantom for evaluating deformable image registration (DIR) accuracy on images and dose deformation in adaptive radiation therapy (ART). Method: Organ moulds, including liver, kidney, spleen, stomach, vertebra and two metastasis tumors, are 3D printed using the contours from an ovarian cancer patient. The organ moulds are molded with deformable gels that made of different mixtures of polyvinyl chloride (PVC) and the softener dioctyl terephthalate. Gels with different densities are obtained by a polynomial fitting curve which describes the relation between the CT number and PVC-softener blending ratio. The rigid vertebras are constructed by moulding with white cement. The final abdominal phantom is assembled by arranging all the fabricated organs inside a hollow dummy according to their anatomies and sealed with deformable gel with averaged CT number of muscle and fat. Geometric and dosimetric landmarks are embedded inside the phantom for spatial accuracy and dose accumulation accuracy studies. Three DIR algorithms available in the open source DIR toolkit-DIRART, including the Demons, the Horn-Schunck and Lucas-Kanade method and the Level-Set Motion method, are tested using the constructed phantom. Results: Viscoelastic behavior is observed in the constructed deformable gel, which serves as an ideal material for the deformable phantom. The constructed abdominal phantom consists of highly realistic anatomy and the fabricated organs inside have close CT number to its reference patient. DIR accuracy studies conducted on the constructed phantom using three DIR approaches indicate that geometric accuracy of a DIR algorithm has achieved does not guarantee accuracy in dose accumulation. Conclusions: We have designed and constructed an anthropopathic abdominal deformable phantom with satisfactory elastic property, realistic organ density and anatomy. This physical phantom is recyclable and can be used for routine validations of DIR geometric accuracy and dose accumulation accuracy in ART. This work is supported in part by grant from VARIAN MEDICAL SYSTEMS INC, the National Natural Science Foundation of China (no 81428019 and no 81301940), the Guangdong Natural Science Foundation (2015A030313302) and the 2015 Pearl River S&T Nova Program of Guangzhou (201506010096).

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Brucella Periplasmic Protein EipB Is a Molecular Determinant of Cell Envelope Integrity and Virulence

The Gram-negative cell envelope is a remarkable structure with core components that include an inner membrane, an outer membrane, and a peptidoglycan layer in the periplasmic space between. Multiple molecular systems function to maintain integrity of this essential barrier between the interior of the cell and its surrounding environment. Herein, we show that a conserved DUF1849 family protein, EipB, is secreted to the periplasmic space of Brucella species, a monophyletic group of intracellular pathogens. In the periplasm, EipB folds into an unusual 14-stranded β-spiral structure that resembles the LolA and LolB lipoprotein delivery system, though the overall fold of EipB is distinct from LolA/LolB. Deletion of eipB results in defects in Brucella cell envelope integrity in vitro and in maintenance of spleen colonization in a mouse model of Brucella abortus infection. Transposon disruption of ttpA, which encodes a periplasmic protein containing tetratricopeptide repeats, is synthetically lethal with eipB deletion. ttpA is a reported virulence determinant in Brucella, and our studies of ttpA deletion and overexpression strains provide evidence that this gene also contributes to cell envelope function. We conclude that eipB and ttpA function in the Brucella periplasmic space to maintain cell envelope integrity, which facilitates survival in a mammalian host.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

WrpA Is an Atypical Flavodoxin Family Protein under Regulatory Control of the Brucella abortus General Stress Response System

ABSTRACT The general stress response (GSR) system of the intracellular pathogen Brucella abortus controls the transcription of approximately 100 genes in response to a range of stress cues. The core genetic regulatory components of the GSR are required for B. abortus survival under nonoptimal growth conditions in vitro and for maintenance of chronic infection in an in vivo mouse model. The functions of the majority of the genes in the GSR transcriptional regulon remain undefined. bab1_1070 is among the most highly regulated genes in this regulon: its transcription is activated 20- to 30-fold by the GSR system under oxidative conditions in vitro . We have solved crystal structures of Bab1_1070 and demonstrate that it forms a homotetrameric complex that resembles those of WrbA-type NADH:quinone oxidoreductases, which are members of the flavodoxin protein family. However, B. abortus W rbA- r elated p rotein (WrpA) does not bind flavin cofactors with a high affinity and does not function as an NADH:quinone oxidoreductase in vitro . Soaking crystals with flavin mononucleotide (FMN) revealed a likely low-affinity binding site adjacent to the canonical WrbA flavin binding site. Deletion of wrpA (Δ wrpA ) does not compromise cell survival under acute oxidative stress in vitro or attenuate infection in cell-based or mouse models. However, a Δ wrpA strain does elicit increased splenomegaly in a mouse model, suggesting that WrpA modulates B. abortus interaction with its mammalian host. Despite high structural homology with canonical WrbA proteins, we propose that B. abortus WrpA represents a functionally distinct member of the diverse flavodoxin family. IMPORTANCE Brucella abortus is an etiological agent of brucellosis, which is among the most common zoonotic diseases worldwide. The general stress response (GSR) regulatory system of B. abortus controls the transcription of approximately 100 genes and is required for maintenance of chronic infection in a murine model; the majority of GSR-regulated genes remain uncharacterized. We present in vitro and in vivo functional and structural analyses of WrpA, whose expression is strongly induced by GSR under oxidative conditions. Though WrpA is structurally related to NADH:quinone oxidoreductases, it does not bind redox cofactors in solution, nor does it exhibit oxidoreductase activity in vitro . However, WrpA does affect spleen inflammation in a murine infection model. Our data provide evidence that WrpA forms a new functional class of WrbA/flavodoxin family proteins.

Herrou, Julien↗