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All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

EGF–FGF{sub 2} stimulates the proliferation and improves the neuronal commitment of mouse epidermal neural crest stem cells (EPI-NCSCs)

Epidermal neural crest stem cells (EPI-NCSCs), which reside in the bulge of hair follicles, are attractive candidates for several applications in cell therapy, drug screening and tissue engineering. As suggested remnants of the embryonic neural crest (NC) in an adult location, EPI-NCSCs are able to generate a wide variety of cell types and are readily accessible by a minimally invasive procedure. Since the combination of epidermal growth factor (EGF) and fibroblast growth factor type 2 (FGF{sub 2}) is mitogenic and promotes the neuronal commitment of various stem cell populations, we examined its effects in the proliferation and neuronal potential of mouse EPI-NCSCs. By using a recognized culture protocol of bulge whiskers follicles, we were able to isolate a population of EPI-NCSCs, characterized by the migratory potential, cell morphology and expression of phenotypic markers of NC cells. EPI-NCSCs expressed neuronal, glial and smooth muscle markers and exhibited the NC-like fibroblastic morphology. The treatment with the combination EGF and FGF{sub 2}, however, increased their proliferation rate and promoted the acquisition of a neuronal-like morphology accompanied by reorganization of neural cytoskeletal proteins βIII-tubulin and nestin, as well as upregulation of the pan neuronal marker βIII-tubulin and down regulation of the undifferentiated NC, glial and smooth muscle cell markers. Moreover, the treatment enhanced the response of EPI-NCSCs to neurogenic stimulation, as evidenced by induction of GAP43, and increased expression of Mash-1 in neuron-like cell, both neuronal-specific proteins. Together, the results suggest that the combination of EGF–FGF2 stimulates the proliferation and improves the neuronal potential of EPI-NCSCs similarly to embryonic NC cells, ES cells and neural progenitor/stem cells of the central nervous system and highlights the advantage of using EGF–FGF{sub 2} in neuronal differentiation protocols. - Highlights: • EPI-NCSCs express undifferentiated NC and lineage-specific markers. • EGF–FGF{sub 2} supports in vitro expansion of EPI-NCSCs. • EGF–FGF{sub 2} promotes acquisition of neuron-like morphology by EPI-NCSCs. • EGF–FGF{sub 2} up regulates the expression of the pan-neuronal marker βIII-tubulin. • EGF–FGF{sub 2} enhances the response of EPI-NCSCs to neurogenic stimulation in vitro.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

A new cell-based assay to evaluate myogenesis in mouse myoblast C2C12 cells

The development of the efficient screening system of detecting compounds that promote myogenesis and prevent muscle atrophy is important. Mouse C2C12 cells are widely used to evaluate myogenesis but the procedures of the assay are not simple and the quantification is not easy. We established C2C12 cells expressing the N-terminal green fluorescence protein (GFP) and the C-terminal GFP (GFP1–10 and GFP11 cells). GFP1–10 and GFP11 cells do not exhibit GFP signals until they are fused. The signal intensity correlates with the expression of myogenic markers and myofusion. Myogenesis-promoting reagents, such as insulin-like growth factor-1 (IGF1) and β-guanidinopropionic acid (GPA), enhance the signals, whereas the poly-caspase inhibitor, z-VAD-FMK, suppresses it. GFP signals are observed when myotubes formed by GFP1–10 cells are fused with single nuclear GFP11 cells, and enhanced by IGF1, GPA, and IBS008738, a recently-reported myogenesis-promoting reagent. Fusion between myotubes formed by GFP1–10 and GFP11 cells is associated with the appearance of GFP signals. IGF1 and GPA augment these signals, whereas NSC23766, Rac inhibitor, decreases them. The conditioned medium of cancer cells suppresses GFP signals during myogenesis and reduces the width of GFP-positive myotubes after differentiation. Thus the novel split GFP-based assay will provide the useful method for the study of myogenesis, myofusion, and atrophy. - Highlights: • C2C12 cells expressing split GFP proteins show GFP signals when mix-cultured. • The GFP signals correlate with myogenesis and myofusion. • The GFP signals attenuate under the condition that muscle atrophy is induced.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Polymer microfiber meshes facilitate cardiac differentiation of c-kit{sup +} human cardiac stem cells

Electrospun microfiber meshes have been shown to support the proliferation and differentiation of many types of stem cells, but the phenotypic fate of c-kit{sup +} human cardiac stem cells (hCSCs) have not been explored. To this end, we utilized thin (~5 µm) elastomeric meshes consisting of aligned 1.7 µm diameter poly (ester-urethane urea) microfibers as substrates to examine their effect on hCSC viability, morphology, proliferation, and differentiation relative to cells cultured on tissue culture polystyrene (TCPS). The results showed that cells on microfiber meshes displayed an elongated morphology aligned in the direction of fiber orientation, lower proliferation rates, but increased expressions of genes and proteins majorly associated with cardiomyocyte phenotype. The early (NK2 homeobox 5, Nkx2.5) and late (cardiac troponin I, cTnI) cardiomyocyte genes were significantly increased on meshes (Nkx=2.5 56.2±13.0, cTnl=2.9±0.56,) over TCPS (Nkx2.5=4.2±0.9, cTnl=1.6±0.5, n=9, p<0.05 for both groups) after differentiation. In contrast, expressions of smooth muscle markers, Gata6 and myosin heavy chain (SM-MHC), were decreased on meshes. Immunocytochemical analysis with cardiac antibody exhibited the similar pattern of above cardiac differentiation. We conclude that aligned microfiber meshes are suitable for guiding cardiac differentiation of hCSCs and may facilitate stem cell-based therapies for treatment of cardiac diseases. - Highlights: • First study to characterize c-kit{sup +} human cardiac stem cells on microfiber meshes. • Microfiber meshes seem reducing cell proliferation, but no effect on cell viability. • Microfiber meshes facilitate the elongation of human cardiac stem cells in culture. • Cardiac but not smooth muscle differentiation were enhanced on microfiber meshes. • Microfiber meshes may be used as cardiac patches in cell-based cardiac therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Atractylenolide I restores HO-1 expression and inhibits Ox-LDL-induced VSMCs proliferation, migration and inflammatory responses in vitro

Pathogenesis of atherosclerosis is characterized by the proliferation and migration of vascular smooth muscle cells (VSMCs) and inflammatory lesions. The aim of this study is to elucidate the effect of atractylenolide I (AO-I) on smooth muscle cell inflammation, proliferation and migration induced by oxidized modified low density lipoprotein (Ox-LDL). Here, We found that atractylenolide I inhibited Ox-LDL-induced VSMCs proliferation and migration in a dose-dependent manner, and decreased the production of inflammatory cytokines and the expression of monocyte chemoattractant protein-1 (MCP-1) in VSMCs. The study also identified that AO-I prominently inhibited p38-MAPK and NF-κB activation. More importantly, the specific heme oxygenase-1 (HO-1) inhibitor zinc protoporphyrin (ZnPP) IX partially abolished the beneficial effects of atractylenolide I on Ox-LDL-induced VSMCs. Furthermore, atractylenolide I blocked the foam cell formation in macrophages induced by Ox-LDL. In summary, inhibitory roles of AO-I in VSMCs proliferation and migration, lipid peroxidation and subsequent inflammatory responses might contribute to the anti-atherosclerotic property of AO-I. - Highlights: • AO-I inhibited Ox-LDL-induced VSMCs proliferation and migration. • AO-I alleviated inflammatory response via inhibiting TNF-α, IL-6 and NO production. • AO-I restored HO-1 expression and down-regulated PCNA expression. • MCP-1 overexpression is potentially regulated by NF-κB and p38 MAPK pathway. • AO-I possesses strong anti-lipid peroxidation effect.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

β-catenin is important for the development of an insulin responsive pool of GLUT4 glucose transporters in 3T3-L1 adipocytes

GLUT4 is unique among specialized glucose transporters in being exclusively expressed in muscle and adipocytes. In the absence of insulin the distribution of GLUT4 is preferentially intracellular and insulin stimulation results in the movement of GLUT4 containing vesicles to the plasma membrane. This process is responsible for the insulin stimulation of glucose uptake in muscle and fat. While signalling pathways triggering the translocation of GLUT4 are well understood, the mechanisms regulating the intracellular retention of GLUT4 are less well understood. Here we report a role for β-catenin in this process. In 3T3-L1 adipocytes in which β-catenin is depleted, the levels of GLUT4 at and near the plasma membrane rise in unstimulated cells while the subsequent increase in GLUT4 at the plasma membrane upon insulin stimulation is reduced. Small molecule approaches to acutely activate or inhibit β-catenin give results that support the results obtained with siRNA and these changes are accompanied by matching changes in glucose transport into these cells. Together these results indicate that β-catenin is a previously unrecognized regulator of the mechanisms that control the insulin sensitive pool of GLUT4 transporters inside these adipocyte cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Dexamethasone reduces the formation of thoracic aortic aneurysm and dissection in a murine model

Highlights: • Dexamethasone attenuated thoracic aortic aneurysm and dissection in a mouse model. • Dexamethasone reduced infiltration of inflammatory cell and apoptosis of vascular smooth muscle cell and fibroblast. • Dexamethasone partly alleviated degradation of collagen and phenotype switch. • DEX might ameliorate thoracic aortic aneurysm and dissection by suppressing NF-κB signaling pathway. Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease with no effective pharmaceutical therapies currently available. Inflammation plays a key role in the progression of aneurysms. Dexamethasone (DEX), a synthetic glucocorticoid, has showed alleviating effects on cells in vitro from TAAD patients. Here we performed a study aiming at investigating the protective role of DEX in a β-aminopropionitrile monofumarate (BAPN)-induced TAAD mouse model. DEX (dose: 0.04 mg/kg/day) treatment significantly reduced the aortic diameter and inhibited TAAD formation. DEX reduced infiltration of macrophages and neutrophils, apoptosis of vascular smooth muscle cells (VSMCs), expression of metalloproteinase 2/9, and extracellular matrix degradation in BAPN-treated TAAD mice. Furthermore, DEX therapy downregulated the expression of p-p65 in macrophages and VSMCs, which suggested that DEX might ameliorate BAPN-induced TAAD by suppressing NF-κB signaling. Therefore, DEX therapy attenuates the progression of BAPN-induced TAAD murine model and could be used as an effective adjuvant therapy for treating TAAD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

CRISPR/Cas correction of muscular dystrophies

Muscular dystrophies are a heterogeneous group of monogenic neuromuscular disorders which lead to progressive muscle loss and degeneration of the musculoskeletal system. The genetic causes of muscular dystrophies are well characterized, but no effective treatments have been developed so far. The discovery and application of the CRISPR/Cas system for genome editing offers a new path for disease treatment with the potential to permanently correct genetic mutations. The post-mitotic and multinucleated features of skeletal muscle provide an ideal target for CRISPR/Cas therapeutic genome editing because correction of a subpopulation of nuclei can provide benefit to the whole myofiber. In this review, we provide an overview of the CRISPR/Cas system and its derivatives in genome editing, proposing potential CRISPR/Cas-based therapies to correct diverse muscular dystrophies, and we discuss challenges for translating CRISPR/Cas genome editing to a viable therapy for permanent correction of muscular dystrophies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Challenges in cell transplantation for muscular dystrophy

For decades now, cell transplantation has been considered a possible therapeutic strategy for muscular dystrophy, but failures have largely outnumbered success or at least encouraging outcomes. }In this review we will briefly recall the history of cell transplantation, discuss the peculiar features of skeletal muscle, and dystrophic skeletal muscle in particular, that make the procedure complicated and inefficient. As there are many recent and exhaustive reviews on the various myogenic cell types that have been or will be transplanted, we will only briefly describe them and refer the reader to these reviews. }Finally, we will discuss possible strategies to overcome the hurdles that prevent biological efficacy and hence clinical success.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Impact of holmium fibre laser radiation (λ = 2.1 μm) on the spinal cord dura mater and adipose tissue

The impact of holmium fibre laser radiation on the samples of biologic tissues (dura mater of spinal cord and adipose tissue with interlayers of muscle) is studied. The experimental results are evaluated by the size of carbonisation and coagulation necrosis zones. The experiment shows that in the case of irradiation of the spinal cord dura mater samples the size of carbonisation and coagulation necrosis zones is insignificant. In the adipose tissue the carbonisation zone is also insignificant, but the region of cellular structure disturbance is large. In the muscle tissue the situation is opposite. The cw laser operation provides clinically acceptable degree of destruction in tissue samples with a minimal carbonisation zone. (laser applications in medicine)

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2017

Structural insights into binding of STAC proteins to voltage-gated calcium channels

Excitation–contraction (EC) coupling in skeletal muscle requires functional and mechanical coupling between L-type voltage-gated calcium channels (Ca V 1.1) and the ryanodine receptor (RyR1). Recently, STAC3 was identified as an essential protein for EC coupling and is part of a group of three proteins that can bind and modulate L-type voltage-gated calcium channels. Here, we report crystal structures of tandem-SH3 domains of different STAC isoforms up to 1.2-Å resolution. These form a rigid interaction through a conserved interdomain interface. We identify the linker connecting transmembrane repeats II and III in two different Ca V isoforms as a binding site for the SH3 domains and report a crystal structure of the complex with the STAC2 isoform. Here, the interaction site includes the location for a disease variant in STAC3 that has been linked to Native American myopathy (NAM). Introducing the mutation does not cause misfolding of the SH3 domains, but abolishes the interaction. Disruption of the interaction via mutations in the II–III loop perturbs skeletal muscle EC coupling, but preserves the ability of STAC3 to slow down inactivation of Ca V 1.2.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2013

Technical Note: Contrast solution density and cross section errors in inhomogeneity-corrected dose calculation for breast balloon brachytherapy

Purpose: Recent recommendations by the American Association of Physicists in Medicine Task Group 186 emphasize the importance of understanding material properties and their effect on inhomogeneity-corrected dose calculation for brachytherapy. Radiographic contrast is normally injected into breast brachytherapy balloons. In this study, the authors independently estimate properties of contrast solution that were expected to be incorrectly specified in a commercial brachytherapy dose calculation algorithm. Methods: The mass density and atomic weight fractions of a clinical formulation of radiographic contrast solution were determined using manufacturers' data. The mass density was verified through measurement and compared with the density obtained by the treatment planning system's CT calibration. The atomic weight fractions were used to determine the photon interaction cross section of the contrast solution for a commercial high-dose-rate (HDR) brachytherapy source and compared with that of muscle. Results: The density of contrast solution was 10% less than that obtained from the CT calibration. The cross section of the contrast solution for the HDR source was 1.2% greater than that of muscle. Both errors could be addressed by overriding the density of the contrast solution in the treatment planning system. Conclusions: The authors estimate the error in mass density and cross section parameters used by a commercial brachytherapy dose calculation algorithm for radiographic contrast used in a clinical breast brachytherapy practice. This approach is adaptable to other clinics seeking to evaluate dose calculation errors and determine appropriate density override values if desired.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-E-J-203: Investigation of 1.5T Magnetic Field Dose Effects On Organs of Different Density

Purpose: For the combined 1.5T/6MV MRI-linac system, the perpendicular magnetic field to the radiation beam results in altered radiation dose distributions. This Monte Carlo study investigates the change in dose at interfaces for common organs neighboring soft tissue. Methods: MCNP6 was used to simulate the effects of a 1.5T magnetic field when irradiating tissues with a 6 MV beam. The geometries used in this study were not necessarily anatomically representative in size in order to directly compare quantitative dose effects for each tissue at the same depths. For this purpose, a 512 cm{sup 3} cubic material was positioned at the center of a 2744 cm{sup 3} cubic soft tissue material phantom. The following tissue materials and their densities were used in this study: lung (0.296 g/cm{sup 3}), fat (0.95), spinal cord (1.038), soft tissue (1.04), muscle (1.05), eye (1.076), trabecular bone (1.40), and cortical bone (1.85). Results: The addition of a 1.5T magnetic field caused dose changes of +46.5%, +2.4%, −0.9%, −0.8%, −1.5%, −6.5%, and −8.8% at the entrance interface between soft tissue and lung, fat, spinal cord, muscle, eye, trabecular bone, and cortical bone tissues respectively. Dose changes of −39.4%, −4.1%, −0.8%, −0.8%, +0.5%, +6.7%, and +10.9% were observed at the second interface between the same tissues respectively and soft tissue. On average, the build-up distance was reduced by 0.6 cm, and a dose increase of 62.7% was observed at the exit interface between soft tissue and air of the entire phantom. Conclusion: The greatest changes in dose were observed at interfaces containing lung and bone tissues. Due to the prevalence and proximity of bony anatomy to soft tissues throughout the human body, these results encourage further examination of these tissues with anatomically representative geometries using multiple beam configurations for safe treatment using the MRI-linac system.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Intercostal high intensity focused ultrasound for liver ablation: The influence of beam shaping on sonication efficacy and near-field risks

Purpose: One of the major issues in high intensity focused ultrasound ablation of abdominal lesions is obstruction of the ultrasound beam by the thoracic cage. Beam shaping strategies have been shown by several authors to increase focal point intensity while limiting rib exposure. However, as rib obstruction leaves only part of the aperture available for energy transmission, conserving total emitted acoustic power, the intensity in the near-field tissues inherently increases after beam shaping. Despite of effective rib sparing, those tissues are therefore subjected to increased risk of thermal damage. In this study, for a number of clinically representative intercostal sonication geometries, modeling clinically available hardware, the effect of beam shaping on both the exposure of the ribs and near-field to acoustic energy was evaluated and the implications for the volumetric ablation rate were addressed. Methods: A relationship between rib temperature rise and acoustic energy density was established by means of in vivo MR thermometry and simulations of the incident acoustic energy for the corresponding anatomies. This relationship was used for interpretation of rib exposure in subsequent numerical simulations in which rib spacing, focal point placement, and the focal point trajectory were varied. The time required to heat a targeted region to 65 °C was determined without and with the application of beam shaping. The required sonication time was used to calculate the acoustic energy density at the fat–muscle interface and at the surface of the ribs. At the fat–muscle interface, exposure was compared to available literature data and rib exposure was interpreted based on the earlier obtained relation between measured temperature rise and simulated acoustic energy density. To estimate the volumetric ablation rate, the cool-down time between periods of energy exposure was estimated using a time-averaged power limit of 100 kJ/h. Results: At the level of the ribs, the temperature rise–energy density proportionality constant was estimated to be 6.0–7.6 °C/(J/mm{sup 2}). Beam shaping by the geometric shadow method typically reduces the acoustic intensity a factor of 2, considering the 1 cm{sup 2} with the highest exposure. For a 4 mm diameter circular sonication trajectory, the near-field energy limit of 2.5 J/mm{sup 2} was exceeded for all considered geometries. The estimated rib temperature was in all but one (sonication 50 mm behind the ribs, with 15 mm rib spacing and a 4 mm diameter circular sonication trajectory) of the considered scenarios within acceptable limits. For those sonication scenarios where a single sonication is considered safe both in terms of near-field as well as rib heating, volumetric ablation rates in the order of 1 ml/h are estimated. Conclusions: Intercostal sonication is associated with an increased risk of near-field overheating. This risk is strongly dependent on the considered rib spacing, the placement of the focus behind the ribs, and the selected sonication trajectory. For the hardware under simulation, obstruction by the thoracic cage renders ablations of clinically relevant volumes within a practical time-frame unfeasible in a large part of the liver. Improvements maybe expected from transducer designs with a larger active surface and/or nonlinear sonication strategies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

MO-F-CAMPUS-I-05: Quantitative ADC Measurement of Esophageal Cancer Before and After Chemoradiation

Purpose: We investigated whether quantitative diffusion imaging can be used as an imaging biomarker for early prediction of treatment response of esophageal cancer. Methods: Eight patients with esophageal cancer underwent a baseline and an interim MRI studies during chemoradiation on a 3T whole body MRI scanner with an 8-channel torso phased array coil. Each MRI study contained two axial diffusion-weighted imaging (DWI) series with a conventional DWI sequence and a reduced field-of-view DWI sequence (FOCUS) of varying b-values. ADC maps with two b-values were computed from conventional DWI images using a mono-exponential model. For each of DWI sequences, separate ADCall was computed by fitting the signal intensity of images with all the b-values to a single exponential model. For the FOCUS sequence, a bi-exponential model was used to extract perfusion and diffusion coefficients (ADCperf and ADCdiff) and their contributions to the signal decay. A board-certified radiologist contoured the tumor region and mean ADC values and standard deviations of tumor and muscle ROIs were recorded from different ADC maps. Results: Our results showed that (1) the magnitude of ADCs from the same ROIs by the different analysis methods can be substantially different. (2) For a given method, the change between the baseline and interim muscle ADCs was relatively small (≤10%). In contrast, the change between the baseline and interim tumor ADCs was substantially larger, with the change in ADCdiff by FOCUS DWI showing the largest percentage change of 73.2%. (3) The range of the relative change of a specific parameter for different patients was also different. Conclusion: Presently, we do not have the final pathological confirmation of the treatment response for all the patients. However, for a few patients whose surgical specimen is available, the quantitative ADC changes have been found to be useful as a potential predictor for treatment response.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Comparison of organ-at-risk sparing and plan robustness for spot-scanning proton therapy and volumetric modulated arc photon therapy in head-and-neck cancer

Purpose: Proton radiotherapy for head-and-neck cancer (HNC) aims to improve organ-at-risk (OAR) sparing over photon radiotherapy. However, it may be less robust for setup and range uncertainties. The authors investigated OAR sparing and plan robustness for spot-scanning proton planning techniques and compared these with volumetric modulated arc therapy (VMAT) photon plans. Methods: Ten HNC patients were replanned using two arc VMAT (RapidArc) and spot-scanning proton techniques. OARs to be spared included the contra- and ipsilateral parotid and submandibular glands and individual swallowing muscles. Proton plans were made using Multifield Optimization (MFO, using three, five, and seven fields) and Single-field Optimization (SFO, using three fields). OAR sparing was evaluated using mean dose to composite salivary glands (Comp{sub Sal}) and composite swallowing muscles (Comp{sub Swal}). Plan robustness was determined for setup and range uncertainties (±3 mm for setup, ±3% HU) evaluating V95% and V107% for clinical target volumes. Results: Averaged over all patients Comp{sub Sal}/Comp{sub Swal} mean doses were lower for the three-field MFO plans (14.6/16.4 Gy) compared to the three-field SFO plans (20.0/23.7 Gy) and VMAT plans (23.0/25.3 Gy). Using more than three fields resulted in differences in OAR sparing of less than 1.5 Gy between plans. SFO plans were significantly more robust than MFO plans. VMAT plans were the most robust. Conclusions: MFO plans had improved OAR sparing but were less robust than SFO and VMAT plans, while SFO plans were more robust than MFO plans but resulted in less OAR sparing. Robustness of the MFO plans did not increase with more fields.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-D-BRA-01: Feasibility Study for Swallowing Prediction Using Pressure Sensors

Purpose: To develop a swallowing prediction system (SPS) using force sensing sensors and evaluate its feasibility. Methods: The SPS developed consists of force sensing sensor units, a thermoplastic mask, a signal transport device and a control PC installed with an in-house software. The SPS is designed to predict the pharyngeal stage of swallowing because it is known that internal organ movement occurs in pharyngeal stage. To detect prediction signal in the SPS, the force sensing sensor units were attached on both the submental muscle region and thyroid cartilage region of the thermoplastic mask. While the signal from the thyroid cartilage region informs the action of swallowing, the signal from the submental muscle region is utilized as a precursor for swallowing. Since the duration of swallowing is relatively short, using such precursor (or warning) signals for machine control is considered more beneficial. A volunteer study was conducted to evaluate the feasibility of the system. In this volunteer study, we intended to verify that the system could predict the pharyngeal stage of the swallowing. We measured time gaps between obtaining the warning signals in the SPS and starting points of the pharyngeal stage of swallowing. Results: The measured data was examined whether the time gaps were in reasonable order to be easily utilized. The mean and standard deviation values of these time gaps were 0.550 s ± 0.183 s. in 8 volunteers. Conclusion: The proposed method was able to predict the on-set of swallowing of human subjects inside the thermoplastic mask, which has never been possible with other monitoring systems such as camera-based monitoring system. With the prediction ability of swallowing incorporated into the machine control mechanism (in the future), beam delivery can be controlled to skip swallowing periods and significant dosimetric gain is expected in head & neck cancer treatments. This work was supported by the Radiation Technology R&D program (No. 2015M2A2A7038291) and by the Mid-career Researcher Program (2014R1A2A1A10050270) through the National Research Foundation of Korea funded by the Ministry of Science, ICT&Future Planning.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-D-207A-03: Potential Role of BOLD MRI in Discrimination of Aggressive Tumor Habitat in Prostate Cancer

Purpose: To determine whether blood oxygenation level dependent (BOLD) MRI signal measured in prostate cancer patients, in addition to quantitative diffusion and perfusion parameters from multiparametric (mp)MRI exams, can help discriminate aggressive and/or radioresistant lesions. Methods: Several ongoing clinical trials in our institution require mpMRI exam to determine eligibility (presence of identifiable tumor lesion on mpMRI) and prostate volumes for dose escalation. Upon consent, patients undergo fiducial markers placement and a T2*-weighted imaging at the time of CT sim to facilitate the fusion. In a retrospective analysis eleven clinical trial patients were identified who had undergone mpMRI on GE 3T magnet, followed by T2*-weighted imaging (time-period mean±SD = 48±20 days) using a consistent protocol (gradient echo, TR/TE=30/11.8ms, flip angle=12, matrix=256×256×75, voxel size=1.25×1.25×2.5mm). ROIs for prostate tumor lesions were automatically determined using ADC threshold ≤1200 µm2/s. Although the MR protocol was not intended for BOLD analysis, we utilized the T2*-weighted signal normalized to that in nearby muscle; likewise, T2-weighted lesion signal was normalized to muscle, following rigid registration of the T2 to T2* images. The ratio of these normalized signals, T2*/T2, is a measure of BOLD effect in the prostate tumors. Perfusion parameters (Ktrans, ve, kep) were also calculated. Results: T2*/T2 (mean±SE) was found to be substantially lower for Gleason score (GS) 8&9 (0.82±0.04) compared to GS 7 (1.08±0.07). A k-means cluster analysis of T2*/T2 versus kep = Ktrans/ve revealed two distinct clusters, one with higher T2*/T2 and lower kep, containing only GS 7 lesions, and another with lower T2*/T2 and higher kep, associated with tumor aggressiveness. This latter cluster contained all GS 8&9 lesions, as well as some GS 7. Conclusion: BOLD MRI, in addition to ADC and kep, may play a role (perhaps orthogonal to Gleason score) in identifying prostate lesions that would benefit from more aggressive radiotherapy.

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↗