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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
DOE OSTI2011

Preclinical Assessment of Volumetric Modulated Arc Therapy for Total Marrow Irradiation

Purpose: A preclinical investigation was undertaken to explore a treatment technique for total marrow irradiation using RapidArc, a volumetric modulated arc technique. Materials and Methods: Computed tomography datasets of 5 patients were included. Plans with eight overlapping coaxial arcs were optimized for 6-MV photon beams. Dose prescription was 12 Gy in 2 Gy per fraction, normalized so that 100% isodose covered 85% of the planning target volume (PTV). The PTV consisted of the whole skeleton (including ribs and sternum), from the top of the skull to the medium distal third of the femurs. Planning objectives for organs at risk (OARs) were constrained to a median dose <6 to 7 Gy. OARs included brain, eyes, oral cavity, parotids, thyroid, lungs, heart, kidneys, liver, spleen, stomach, abdominal cavity, bladder, rectum, and genitals. Pretreatment quality assurance consisted of portal dosimetry comparisons, scoring the delivery to calculation agreement with the gamma agreement index. Results: The median total body volume in the study was 57 liters (range, 49-81 liters), for an average diameter of 47 cm (range, 46-53 cm) and a total length ranging from 95 to 112 cm. The median PTV volume was 6.8 liters (range, 5.8-10.8 liters). The mean dose to PTV was 109% (range, 107-112%). The global mean of median dose to all OARs was 4.9 Gy (range, 4.5-5.1 Gy over the 5 patients). The individual mean of median doses per organ ranged from 2.3 Gy (oral cavity) to 7.3 Gy (bowels cavity). Preclinical quality assurance resulted in a mean gamma agreement index of 94.3 {+-} 5.1%. The delivery time measured from quality assurance runs was 13 minutes. Conclusion: Sparing of normal tissues with adequate coverage of skeletal bones was shown to be feasible with RapidArc. Pretreatment quality assurance measurements confirmed the technical agreement between expected and actually delivered dose distributions, suggesting the possibility of incorporating this technique in the treatment options for patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Protons Offer Reduced Normal-Tissue Exposure for Patients Receiving Postoperative Radiotherapy for Resected Pancreatic Head Cancer

Purpose: To determine the potential role for adjuvant proton-based radiotherapy (PT) for resected pancreatic head cancer. Methods and Materials: Between June 2008 and November 2008, 8 consecutive patients with resected pancreatic head cancers underwent optimized intensity-modulated radiotherapy (IMRT) treatment planning. IMRT plans used between 10 and 18 fields and delivered 45 Gy to the initial planning target volume (PTV) and a 5.4 Gy boost to a reduced PTV. PTVs were defined according to the Radiation Therapy Oncology Group 9704 radiotherapy guidelines. Ninety-five percent of PTVs received 100% of the target dose and 100% of the PTVs received 95% of the target dose. Normal tissue constraints were as follows: right kidney V18 Gy to <70%; left kidney V18 Gy to <30%; small bowel/stomach V20 Gy to <50%, V45 Gy to <15%, V50 Gy to <10%, and V54 Gy to <5%; liver V30 Gy to <60%; and spinal cord maximum to 46 Gy. Optimized two- to three-field three-dimensional conformal proton plans were retrospectively generated on the same patients. The team generating the proton plans was blinded to the dose distributions achieved by the IMRT plans. The IMRT and proton plans were then compared. A Wilcoxon paired t-test was performed to compare various dosimetric points between the two plans for each patient. Results: All proton plans met all normal tissue constraints and were isoeffective with the corresponding IMRT plans in terms of PTV coverage. The proton plans offered significantly reduced normal-tissue exposure over the IMRT plans with respect to the following: median small bowel V20 Gy, 15.4% with protons versus 47.0% with IMRT (p = 0.0156); median gastric V20 Gy, 2.3% with protons versus 20.0% with IMRT (p = 0.0313); and median right kidney V18 Gy, 27.3% with protons versus 50.5% with IMRT (p = 0.0156). Conclusions: By reducing small bowel and stomach exposure, protons have the potential to reduce the acute and late toxicities of postoperative chemoradiation in this setting.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Dose-Volume Analysis of Predictors for Gastrointestinal Toxicity After Concurrent Full-Dose Gemcitabine and Radiotherapy for Locally Advanced Pancreatic Adenocarcinoma

Purpose: To identify dosimetric predictors for the development of gastrointestinal (GI) toxicity in patients with locally advanced pancreatic adenocarcinoma (LAPC) treated with concurrent full-dose gemcitabine and radiotherapy (GemRT). Methods and Materials: From June 2002 to June 2009, 46 LAPC patients treated with definitive GemRT were retrospectively analyzed. The stomach and duodenum were retrospectively contoured separately to determine their dose-volume histogram (DVH) parameters. GI toxicity was defined as Grade 3 or higher GI toxicity. The follow-up time was calculated from the start of RT to the date of death or last contact. Univariate analysis (UVA) and multivariate analysis (MVA) using Kaplan-Meier and Cox regression models were performed to identify risk factors associated with GI toxicity. The receiver operating characteristic curve and the area under the receiver operating characteristic curve (AUC) were used to determine the best DVH parameter to predict for GI toxicity. Results: Of the patients, 28 (61%) received concurrent gemcitabine alone, and 18 (39%) had concurrent gemcitabine with daily erlotinib. On UVA, only the V{sub 20Gy} to V{sub 35Gy} of duodenum were significantly associated with GI toxicity (all p {<=} 0.05). On MVA, the V{sub 25Gy} of duodenum and the use of erlotinib were independent risk factors for GI toxicity (p = 0.006 and 0.02, respectively). For the entire cohort, the V{sub 25Gy} of duodenum is the best predictor for GI toxicity (AUC = 0.717), and the 12-month GI toxicity rate was 8% vs. 48% for V{sub 25Gy} {<=} 45% and V{sub 25Gy} > 45%, respectively (p = 0.03). However, excluding the erlotinib group, the V{sub 35Gy} is the best predictor (AUC = 0.725), and the 12-month GI toxicity rate was 0% vs. 41% for V{sub 35Gy} {<=} 20% and V{sub 35Gy} > 20%, respectively (p = 0.04). Conclusions: DVH parameters of duodenum may predict Grade 3 GI toxicity after GemRT for LAPC. Concurrent use of erlotinib during GemRT may increase GI toxicity.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Comparison of Heart and Coronary Artery Doses Associated With Intensity-Modulated Radiotherapy Versus Three-Dimensional Conformal Radiotherapy for Distal Esophageal Cancer

Purpose: To compare heart and coronary artery radiation exposure using intensity-modulated radiotherapy (IMRT) vs. four-field three-dimensional conformal radiotherapy (3D-CRT) treatment plans for patients with distal esophageal cancer undergoing chemoradiation. Methods and Materials: Nineteen patients with distal esophageal cancers treated with IMRT from March 2007 to May 2008 were identified. All patients were treated to 50.4 Gy with five-field IMRT plans. Theoretical 3D-CRT plans with four-field beam arrangements were generated. Dose-volume histograms of the planning target volume, heart, right coronary artery, left coronary artery, and other critical normal tissues were compared between the IMRT and 3D-CRT plans, and selected parameters were statistically evaluated using the Wilcoxon rank-sum test. Results: Intensity-modulated radiotherapy treatment planning showed significant reduction (p < 0.05) in heart dose over 3D-CRT as assessed by average mean dose (22.9 vs. 28.2 Gy) and V30 (24.8% vs. 61.0%). There was also significant sparing of the right coronary artery (average mean dose, 23.8 Gy vs. 35.5 Gy), whereas the left coronary artery showed no significant improvement (mean dose, 11.2 Gy vs. 9.2 Gy), p = 0.11. There was no significant difference in percentage of total lung volume receiving at least 10, 15, or 20 Gy or in the mean lung dose between the planning methods. There were also no significant differences observed for the kidneys, liver, stomach, or spinal cord. Intensity-modulated radiotherapy achieved a significant improvement in target conformity as measured by the conformality index (ratio of total volume receiving 95% of prescription dose to planning target volume receiving 95% of prescription dose), with the mean conformality index reduced from 1.56 to 1.30 using IMRT. Conclusions: Treatment of patients with distal esophageal cancer using IMRT significantly decreases the exposure of the heart and right coronary artery when compared with 3D-CRT. Long-term studies are necessary to determine how this will impact on development of coronary artery disease and other cardiac complications.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Radiotherapy Technical Considerations in the Management of Locally Advanced Pancreatic Cancer: American-French Consensus Recommendations

Summary: Pancreatic carcinoma is a leading cause of cancer-related mortality. Approximately 30% of pancreatic cancer patients present with locally advanced, unresectable nonmetastatic disease. For these patients, two therapeutic options exist: systemic chemotherapy or chemoradiotherapy. Within this context, the optimal technique for pancreatic irradiation is not clearly defined. A search to identify relevant studies was undertaken using the Medline database. All Phase III randomized trials evaluating the modalities of radiotherapy in locally advanced pancreatic cancer were included, as were some noncontrolled Phase II and retrospective studies. An expert panel convened with members of the Radiation Therapy Oncology Group and GERCOR cooperative groups to review identified studies and prepare the guidelines. Each member of the working group independently evaluated five endpoints: total dose, target volume definition, radiotherapy planning technique, dose constraints to organs at risk, and quality assurance. Based on this analysis of the literature, we recommend either three-dimensional conformal radiation therapy or intensity-modulated radiation therapy to a total dose of 50 to 54 Gy at 1.8 to 2 Gy per fraction. We propose gross tumor volume identification to be followed by an expansion of 1.5 to 2 cm anteriorly, posteriorly, and laterally, and 2 to 3 cm craniocaudally to generate the planning target volume. The craniocaudal margins can be reduced with the use of respiratory gating. Organs at risk are liver, kidneys, spinal cord, stomach, and small bowel. Stereotactic body radiation therapy should not be used for pancreatic cancer outside of clinical trials. Radiotherapy quality assurance is mandatory in clinical trials. These consensus recommendations are proposed for use in the development of future trials testing new chemotherapy combinations with radiotherapy. Not all of these recommendations will be appropriate for trials testing radiotherapy dose or dose intensity concepts.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Quantifying the Interfractional Displacement of the Gastroesophageal Junction During Radiation Therapy for Esophageal Cancer

Purpose: Accounting for interfractional changes in tumor location improves the accuracy of radiation treatment delivery. The purpose of this study was to quantify the interfractional displacement of the gastroesophageal junction (GEJ) based on standard treatment setup in patients with esophageal cancer undergoing radiation therapy. Methods and Materials: Free-breathing four-dimensional computed tomography (4D-CT) datasets were acquired weekly from 22 patients during treatment for esophageal adenocarcinoma. Scans were registered to baseline (simulation) 4D-CT scans by using bony landmarks. The distance between the center of the GEJ contour on the simulation scan and the mean location of GEJ centers on subsequent scans was used to assess changes in GEJ location between fractions; displacement was also correlated with clinical and respiratory variables. Results: The mean absolute random error was 1.69 mm (range, 0.11-4.11 mm) in the lateral direction, 1.87 mm (range, 0.51-4.09 mm) in the anterior-posterior (AP) direction, and 3.09 mm (range, 0.99-6.16 mm) in the superior-inferior (SI) direction. The mean absolute systemic GEJ displacement between fractions was 2.88 mm lateral ({>=}5 mm in 14%), mostly leftward; 2.90 mm ({>=}5 mm in 14%) AP, mostly anterior; and 6.77 mm ({>=}1 cm in 18%) SI, mostly inferior. Variations in tidal volume and diaphragmatic excursion during treatment correlated strongly with systematic SI GEJ displacement (r = 0.964, p < 0.0001; and r = 0.944, p < 0.0001, respectively) and moderately with systematic AP GEJ displacement (r = 0.678, p = 0.0005; r = 0.758, p < 0.0001, respectively). Systematic displacement in the inferior direction resulted in higher-than-intended doses ({>=}60 Gy) to the GEJ, with increased hot-spot to the adjacent stomach and lung base. Conclusion: We found large (>1-cm) interfractional displacements in the GEJ in the SI (especially inferior) direction that was not accounted for when skeletal alignment alone was used for patient positioning. Because systematic displacement in the SI direction had dosimetric impact and correlated with tidal volume, better accounting for depth of breathing is needed to reduce interfractional variability.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Characterization and Management of Interfractional Anatomic Changes for Pancreatic Cancer Radiotherapy

Purpose: To quantitatively characterize interfractional anatomic variations in pancreatic cancer radiotherapy (RT) and to study dosimetric advantages for using an online adaptive replanning scheme to account for these variations. Methods and Materials: Targets and organs at risk (OAR) were delineated by autosegmentation based on daily computed tomography (CT) images acquired using a respiration-gated in-room CT during daily image-guided RT (IGRT) for 10 pancreatic cancer patients. Various parameters, including the maximum overlap ratio (MOR) between the volumes based on planning and daily CTs for a structure, while the overlapping volumes were maximized, were used to quantify the interfractional organ deformation with the intrafractional variations largely excluded. An online adaptive RT (ART) was applied to these daily CTs. To evaluate the dosimetric benefits of ART, the dose distributions from the online ART were compared to those from the repositioning in the current standard IGRT practice. Results: The interfractional anatomic variations, particularly the organ deformation, are significant during pancreas irradiation. For the patients studied, the average MORs of all daily CTs were 80.2%, 61.7%, and 72.2% for pancreatic head, duodenum, and stomach, respectively. The online ART leads to improved dosimetric plan with better target coverage and/or OAR sparing than IGRT repositioning. For the patients studied, the mean V{sub 50.4Gy} (volume covered by 50.4 Gy) for the duodenum was reduced from 43.4% for IGRT to 15.6% for the online ART scheme. Conclusions: The online adaptive RT scheme can effectively account for the significant interfractional anatomic variations observed in pancreas irradiation. The dosimetric advantages with the online ART may enable safe dose escalation in radiation therapy for pancreatic cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Dosimetric Analysis of Radiation-induced Gastric Bleeding

Purpose: Radiation-induced gastric bleeding has been poorly understood. In this study, we described dosimetric predictors for gastric bleeding after fractionated radiation therapy. Methods and Materials: The records of 139 sequential patients treated with 3-dimensional conformal radiation therapy (3D-CRT) for intrahepatic malignancies were reviewed. Median follow-up was 7.4 months. The parameters of a Lyman normal tissue complication probability (NTCP) model for the occurrence of {>=}grade 3 gastric bleed, adjusted for cirrhosis, were fitted to the data. The principle of maximum likelihood was used to estimate parameters for NTCP models. Results: Sixteen of 116 evaluable patients (14%) developed gastric bleeds at a median time of 4.0 months (mean, 6.5 months; range, 2.1-28.3 months) following completion of RT. The median and mean maximum doses to the stomach were 61 and 63 Gy (range, 46-86 Gy), respectively, after biocorrection of each part of the 3D dose distributions to equivalent 2-Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis predicted gastric bleed. Best-fit Lyman NTCP model parameters were n=0.10 and m=0.21 and with TD{sub 50} (normal) = 56 Gy and TD{sub 50} (cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD{sub 50} value for the cirrhosis patients points out their greater sensitivity. Conclusions: This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

4π Non-Coplanar Liver SBRT: A Novel Delivery Technique

Purpose: To improve the quality of liver stereotactic body radiation therapy (SBRT) treatments, a novel 4π framework was developed with accompanying algorithms to optimize non-coplanar beam orientations and fluences. The dose optimization is performed on a patient-specific deliverable beam geometry solution space, parameterized with patient and linear accelerator gantry orientations. Methods and Materials: Beams causing collision between the gantry and the couch or patient were eliminated by simulating all beam orientations using a precise computer assisted design model of the linear accelerator and a human subject. Integrated beam orientation and fluence map optimizations were performed on remaining beams using a greedy column generation method. Testing of the new method was performed on 10 liver SBRT cases previously treated with 50 to 60 Gy in 5 fractions using volumetric modulated arc therapy (VMAT). For each patient, both 14 and 22 non-coplanar fields were selected and optimized to meet the objective of ≥95% of the planning target volume (PTV) covered by 100% of the prescription dose. Doses to organs at risk, normal liver volumes receiving <15 Gy, integral dose, and 50% dose spillage volumes were compared against the delivered clinical VMAT plans. Results: Compared with the VMAT plans, the 4π plans yielded reduced 50% dose spillage volume and integral dose by 22% (range 10%-40%) and 19% (range 13%-26%), respectively. The mean normal liver volume receiving <15 Gy was increased by 51 cc (range 21-107 cc) with a 31% reduction of the mean normal liver dose. Mean doses to the left kidney and right kidney and maximum doses to the stomach and spinal cord were on average reduced by 70%, 51%, 67%, and 64% (P≤.05). Conclusions: This novel 4π non-coplanar radiation delivery technique significantly improved dose gradient, reduced high dose spillage, and improved organ at risk sparing compared with state of the art VMAT plans.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Adaptive Liver Stereotactic Body Radiation Therapy: Automated Daily Plan Reoptimization Prevents Dose Delivery Degradation Caused by Anatomy Deformations

Purpose: To investigate how dose distributions for liver stereotactic body radiation therapy (SBRT) can be improved by using automated, daily plan reoptimization to account for anatomy deformations, compared with setup corrections only. Methods and Materials: For 12 tumors, 3 strategies for dose delivery were simulated. In the first strategy, computed tomography scans made before each treatment fraction were used only for patient repositioning before dose delivery for correction of detected tumor setup errors. In adaptive second and third strategies, in addition to the isocenter shift, intensity modulated radiation therapy beam profiles were reoptimized or both intensity profiles and beam orientations were reoptimized, respectively. All optimizations were performed with a recently published algorithm for automated, multicriteria optimization of both beam profiles and beam angles. Results: In 6 of 12 cases, violations of organs at risk (ie, heart, stomach, kidney) constraints of 1 to 6 Gy in single fractions occurred in cases of tumor repositioning only. By using the adaptive strategies, these could be avoided (<1 Gy). For 1 case, this needed adaptation by slightly underdosing the planning target volume. For 2 cases with restricted tumor dose in the planning phase to avoid organ-at-risk constraint violations, fraction doses could be increased by 1 and 2 Gy because of more favorable anatomy. Daily reoptimization of both beam profiles and beam angles (third strategy) performed slightly better than reoptimization of profiles only, but the latter required only a few minutes of computation time, whereas full reoptimization took several hours. Conclusions: This simulation study demonstrated that replanning based on daily acquired computed tomography scans can improve liver stereotactic body radiation therapy dose delivery.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Dosimetric benefit of adaptive re-planning in pancreatic cancer stereotactic body radiotherapy

Stereotactic body radiotherapy (SBRT) shows promise in unresectable pancreatic cancer, though this treatment modality has high rates of normal tissue toxicity. This study explores the dosimetric utility of daily adaptive re-planning with pancreas SBRT. We used a previously developed supercomputing online re-planning environment (SCORE) to re-plan 10 patients with pancreas SBRT. Tumor and normal tissue contours were deformed from treatment planning computed tomographies (CTs) and transferred to daily cone-beam CT (CBCT) scans before re-optimizing each daily treatment plan. We compared the intended radiation dose, the actual radiation dose, and the optimized radiation dose for the pancreas tumor planning target volume (PTV) and the duodenum. Treatment re-optimization improved coverage of the PTV and reduced dose to the duodenum. Within the PTV, the actual hot spot (volume receiving 110% of the prescription dose) decreased from 4.5% to 0.5% after daily adaptive re-planning. Within the duodenum, the volume receiving the prescription dose decreased from 0.9% to 0.3% after re-planning. It is noteworthy that variation in the amount of air within a patient's stomach substantially changed dose to the PTV. Adaptive re-planning with pancreas SBRT has the ability to improve dose to the tumor and decrease dose to the nearby duodenum, thereby reducing the risk of toxicity.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2016

A dosimetric comparison of whole-lung treatment techniques in the pediatric population

To demonstrate the dosimetric advantages and disadvantages of standard anteroposterior-posteroanterior (S-AP/PA{sub AAA}), inverse-planned AP/PA (IP-AP/PA) and volumetry-modulated arc (VMAT) radiotherapies in the treatment of children undergoing whole-lung irradiation. Each technique was evaluated by means of target coverage and normal tissue sparing, including data regarding low doses. A historical approach with and without tissue heterogeneity corrections is also demonstrated. Computed tomography (CT) scans of 10 children scanned from the neck to the reproductive organs were used. For each scan, 6 plans were created: (1) S-AP/PA{sub AAA} using the anisotropic analytical algorithm (AAA), (2) IP-AP/PA, (3) VMAT, (4) S-AP/PA{sub NONE} without heterogeneity corrections, (5) S-AP/PA{sub PB} using the Pencil-Beam algorithm and enforcing monitor units from technique 4, and (6) S-AP/PA{sub AAA[FM]} using AAA and forcing fixed monitor units. The first 3 plans compare modern methods and were evaluated based on target coverage and normal tissue sparing. Body maximum and lower body doses (50% and 30%) were also analyzed. Plans 4 to 6 provide a historic view on the progression of heterogeneity algorithms and elucidate what was actually delivered in the past. Averages of each comparison parameter were calculated for all techniques. The S-AP/PA{sub AAA} technique resulted in superior target coverage but had the highest maximum dose to every normal tissue structure. The IP-AP/PA technique provided the lowest dose to the esophagus, stomach, and lower body doses. VMAT excelled at body maximum dose and maximum doses to the heart, spine, and spleen, but resulted in the highest dose in the 30% body range. It was, however, superior to the S-AP/PA{sub AAA} approach in the 50% range. Each approach has strengths and weaknesses thus associated. Techniques may be selected on a case-by-case basis and by physician preference of target coverage vs normal tissue sparing.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2012

Effects of SiC nanoparticles orally administered in a rat model: Biodistribution, toxicity and elemental composition changes in feces and organs

Background: Silicon carbide (SiC) presents noteworthy properties as a material such as high hardness, thermal stability, and photoluminescent properties as a nanocrystal. However, there are very few studies in regard to the toxicological potential of SiC NPs. Objectives: To study the toxicity and biodistribution of silicon carbide (SiC) nanoparticles in an in vivo rat model after acute (24 h) and subacute (28 days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 600 mg·kg{sup −1}, while the subacute doses were 0.5 and 50 mg·kg{sup −1}. Results: SiC biodistribution and elemental composition of feces and organs (liver, kidneys, and spleen) have been studied by Particle-Induced X-ray Emission (PIXE). SiC and other elements in feces excretion increased by the end of the subacute assessment. SiC did not accumulate in organs but some elemental composition modifications were observed after the acute assessment. Histopathological sections from organs (stomach, intestines, liver, and kidneys) indicate the absence of damage at all applied doses, in both assessments. A decrease in the concentration of urea in blood was found in the 50 mg·kg{sup −1} group from the subacute assessment. No alterations in the urine parameters (sodium, potassium, osmolarity) were found. Conclusion: This is the first study that assesses the toxicity, biodistribution, and composition changes in feces and organs of SiC nanoparticles in an in vivo rat model. SiC was excreted mostly in feces and low traces were retrieved in urine, indicating that SiC can cross the intestinal barrier. No sign of toxicity was however found after oral administration. -- Highlights: ► SiC nanoparticles were orally administered to rats in acute and subacute doses. ► SiC was found in low traces in urine. It is mostly excreted in feces within 5 days. ► SiC excretion rate, feces and organ elemental composition change with time. ► No morphological alteration were found on GI tract, liver, kidneys, or spleen. ► Urea increased in blood in the subacute assessment. No change in urine properties.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

EGFR tyrosine kinase inhibitory peptide attenuates Helicobacter pylori-mediated hyper-proliferation in AGS enteric epithelial cells

Helicobacter pylori infection is one of the most critical causes of stomach cancer. The current study was conducted to explore the protective effects of an isolated active peptide H-P-6 (Pro-Gln-Pro-Lys-Val-Leu-Asp-Ser) from microbial hydrolysates of Chlamydomonas sp. against H. pylori-induced carcinogenesis. The peptide H-P-6 has effectively suppressed H. pylori-induced hyper-proliferation and migration of gastric epithelial cells (AGS). However, the peptide did not inhibit the viability of the bacteria or invasion into AGS cells. Therefore, the effect of the peptide on regulating H. pylori-induced molecular signaling was investigated. The results indicated that H. pylori activates the EGFR tyrosine kinase signaling and nuclear translocation of the β-catenin. The EGFR activation has led to the up-regulation of PI3K/Akt signaling pathway. Moreover, the nuclear translocation levels of β-catenin were significantly increased as a result of Akt mediated down-regulation of GSK3/β protein levels in the cytoplasm. Both of these consequences have resulted in increased expression of cell survival and migration related genes such as c-Myc, cyclin-D, MMP-2 and matrilysin. Interestingly, the isolated peptide potently inhibited H. pylori-mediated EGFR activation and thereby down-regulated the subsequent P13K/Akt signaling leading to β-catenin nuclear translocation. The effect of the peptide was confirmed with the use of EGFR tyrosine kinase inhibitor AG1487 and molecular docking studies. Collectively this study identifies a potent peptide which regulates the H. pylori-induced hyper-proliferation and migration of AGS cells at molecular level. - Highlights: • Chlamydomonas sp. derived peptide H-P-6 inhibits H. pylori-induced pathogenesis. • H-P-6 suppresses H. pylori-induced hyper-proliferation and migration of AGS cells. • The peptide inhibits H. pylori-induced EGFR activation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Inhibition of inflammatory mediators contributes to the anti-inflammatory activity of KYKZL-1 via MAPK and NF-κB pathway

KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the anti-inflammatory activity test focusing on its modulation of inflammatory mediators as well as intracellular MAPK and NF-κB signaling pathways. In acute ear edema model, pretreatment with KYKZL-1 (p.o.) dose-dependently inhibited the xylene-induced ear edema in mice with a higher inhibition than diclofenac. In a three-day TPA-induced inflammation, KYKZL-1 also showed significant anti-inflammatory activity with inhibition ranging between 20% and 64%. In gastric lesion test, KYKZL-1 elicited markedly fewer stomach lesions with a low index of ulcer as compared to diclofenac in rats. In further studies, KYKZL-1 was found to significantly inhibit the production of NO, PGE{sub 2}, LTB{sub 4} in LPS challenged RAW264.7, which is parallel to its attenuation of the expression of iNOS, COX-2, 5-LOX mRNAs or proteins and inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB. Taken together, our data indicate that KYKZL-1 comprises dual inhibition of COX and 5-LOX and exerts an obvious anti-inflammatory activity with an enhanced gastric safety profile via simultaneous inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB. - Highlights: • KYKZL-1 is designed to exhibit COX/5-LOX dual inhibition. • KYKZL-1 inhibits NO, PGE{sub 2} and LTB{sub 4} and iNOS, COX-2 and 5-LOX mRNAs and MAPKs. • KYKZL-1 inhibits phosphorylation of MAPKs. • KYKZL-1 inactivates NF-κB pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Toxicogenomic outcomes predictive of forestomach carcinogenesis following exposure to benzo(a)pyrene: Relevance to human cancer risk

Forestomach tumors are observed in mice exposed to environmental carcinogens. However, the relevance of this data to humans is controversial because humans lack a forestomach. We hypothesize that an understanding of early molecular changes after exposure to a carcinogen in the forestomach will provide mode-of-action information to evaluate the applicability of forestomach cancers to human cancer risk assessment. In the present study we exposed mice to benzo(a)pyrene (BaP), an environmental carcinogen commonly associated with tumors of the rodent forestomach. Toxicogenomic tools were used to profile gene expression response in the forestomach. Adult Muta™Mouse males were orally exposed to 25, 50, and 75 mg BaP/kg-body-weight/day for 28 consecutive days. The forestomach was collected three days post-exposure. DNA microarrays, real-time RT-qPCR arrays, and protein analyses were employed to characterize responses in the forestomach. Microarray results showed altered expression of 414 genes across all treatment groups (± 1.5 fold; false discovery rate adjusted P ≤ 0.05). Significant downregulation of genes associated with phase II xenobiotic metabolism and increased expression of genes implicated in antigen processing and presentation, immune response, chemotaxis, and keratinocyte differentiation were observed in treated groups in a dose-dependent manner. A systematic comparison of the differentially expressed genes in the forestomach from the present study to differentially expressed genes identified in human diseases including human gastrointestinal tract cancers using the NextBio Human Disease Atlas showed significant commonalities between the two models. Our results provide molecular evidence supporting the use of the mouse forestomach model to evaluate chemically-induced gastrointestinal carcinogenesis in humans. - Highlights: • Benzo(a)pyrene-mediated transcriptomic response in the forestomach was examined. • The immunoproteosome subunits and MHC class I pathway were the most affected. • Keratinocyte differentiation associated gene expression changes were dose-dependent. • Molecular similarities exist between cancers of the forestomach and human stomach.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Estimation of gastric emptying time (GET) in clownfish (Amphiprion ocellaris) using X-radiography technique

This study examines the movement of food item and the estimation of gastric emptying time using the X-radiography techniques, in the clownfish (Amphiprion ocellaris) fed in captivity. Fishes were voluntarily fed to satiation after being deprived of food for 72 hours, using pellets that were tampered with barium sulphate (BaSO{sub 4}). The movement of food item was monitored over different time of feeding. As a result, a total of 36 hours were needed for the food items to be evacuated completely from the stomach. Results on the modeling of meal satiation were also discussed. The size of satiation meal to body weight relationship was allometric, with the power value equal to 1.28.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2011

Paired organs--Should they be treated jointly or separately in internal dosimetry?

Purpose: Size, shape, and the position of paired organs are different in abdomen. However, the counterpart organs are conventionally treated jointly together in internal dosimetry. This study was performed to quantify the difference of specific absorbed fraction of organs in considering paired organs jointly like single organs or as two separate organs. Methods: Zubal phantom and GATE Monte Carlo package were used to calculate the SAF for the self-absorption and cross-irradiation of the lungs, kidneys, adrenal glands (paired organs), liver, spleen, stomach, and pancreas (single organs). The activity was assumed uniformly distributed in the organs, and simulation was performed for monoenergetic photons of 10, 50, 100, 500, 1000 keV and mono-energetic electrons of 350, 500, 690, 935, 1200 keV. Results: The results demonstrated that self-absorption of left and right counterpart organs may be different depending upon the differences in their masses. The cross-irradiations between left-to-right and right-to-left counterpart organs are always equal irrespective of difference in their masses. Cross-irradiation from the left and right counterpart organs to other organs are different (4-24 times in Zubal phantom) depending on the photon energy and organs. The irradiation from a single source organ to the left and right counterpart paired organs is always different irrespective of activity concentration. Conclusions: Left and right counterpart organs always receive different absorbed doses from target organs and deliver different absorbed doses to target organs. Therefore, in application of radiopharmaceuticals in which the dose to the organs plays a role, counterpart organs should be treated separately as two separate organs.

62 RADIOLOGY AND NUCLEAR MEDICINE↗