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DOE OSTI2014

MO-G-17A-04: Internal Dosimetric Calculations for Pediatric Nuclear Imaging Applications, Using Monte Carlo Simulations and High-Resolution Pediatric Computational Models

Purpose: Our purpose is to evaluate the administered absorbed dose in pediatric, nuclear imaging studies. Monte Carlo simulations with the incorporation of pediatric computational models can serve as reference for the accurate determination of absorbed dose. The procedure of the calculated dosimetric factors is described, while a dataset of reference doses is created. Methods: Realistic simulations were executed using the GATE toolkit and a series of pediatric computational models, developed by the “IT'IS Foundation”. The series of the phantoms used in our work includes 6 models in the range of 5–14 years old (3 boys and 3 girls). Pre-processing techniques were applied to the images, to incorporate the phantoms in GATE simulations. The resolution of the phantoms was set to 2 mm3. The most important organ densities were simulated according to the GATE “Materials Database”. Several used radiopharmaceuticals in SPECT and PET applications are being tested, following the EANM pediatric dosage protocol. The biodistributions of the several isotopes used as activity maps in the simulations, were derived by the literature. Results: Initial results of absorbed dose per organ (mGy) are presented in a 5 years old girl from the whole body exposure to 99mTc - SestaMIBI, 30 minutes after administration. Heart, kidney, liver, ovary, pancreas and brain are the most critical organs, in which the S-factors are calculated. The statistical uncertainty in the simulation procedure was kept lower than 5%. The Sfactors for each target organ are calculated in Gy/(MBq*sec) with highest dose being absorbed in kidneys and pancreas (9.29*10{sup 10} and 0.15*10{sup 10} respectively). Conclusion: An approach for the accurate dosimetry on pediatric models is presented, creating a reference dosage dataset for several radionuclides in children computational models with the advantages of MC techniques. Our study is ongoing, extending our investigation to other reference models and evaluating the results with clinical estimated doses.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Radiotherapy for stage I seminoma of the testis: Organ equivalent dose to partially in-field structures and second cancer risk estimates on the basis of a mechanistic, bell-shaped, and plateau model

Purpose: The aim of the current study was to (a) calculate the organ equivalent dose (OED) and (b) estimate the associated second cancer risk to partially in-field critical structures from adjuvant radiotherapy for stage I seminoma of the testis on the basis of three different nonlinear risk models. Methods: Three-dimensional plans were created for twelve patients who underwent a treatment planning computed tomography of the abdomen. The plans for irradiation of seminoma consisted of para-aortic anteroposterior and posteroanterior fields giving 20 Gy to the target site with 6 MV photons. The OED of stomach, colon, liver, pancreas, and kidneys, that were partially included in the treatment volume, was calculated using differential dose–volume histograms. The mechanistic, bell-shaped, and plateau models were employed for these calculations provided that organ-specific parameters were available for the subsequent assessment of the excess absolute risk (EAR) for second cancer development. The estimated organ-specific lifetime risks were compared with the respective nominal intrinsic probabilities for cancer induction. Results: The mean OED, which was calculated from the patients’ treatment plans, varied from 0.54 to 6.61 Gy by the partially in-field organ of interest and the model used for dosimetric calculations. The difference between the OED of liver derived from the mechanistic model with those from the bell-shaped and plateau models was less than 1.8%. An even smaller deviation of 1.0% was observed for colon. For the rest organs of interest, the differences between the OED values obtained by the examined models varied from 8.6% to 50.0%. The EAR for stomach, colon, liver, pancreas, and kidney cancer induction at an age of 70 yr because of treatment of a typical 39-yr-old individual was up to 4.24, 11.39, 0.91, 3.04, and 0.14 per 10 000 persons-yr, respectively. Patient’s irradiation was found to elevate the lifetime intrinsic risks by 8.3%–63.0% depending upon the organ of interest and the model employed for risk analysis. Conclusions: Radiotherapy for stage I seminoma of the testis may result in an excess risk for the appearance of secondary malignancies in partially in-field organs. The organ- and model-dependent second cancer risk assessments of this study may be of value for patient counseling and follow-up.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Influence of nuclear interactions in body tissues on tumor dose in carbon-ion radiotherapy

Purpose: In carbon-ion radiotherapy treatment planning, the planar integrated dose (PID) measured in water is applied to the patient dose calculation with density scaling using the stopping power ratio. Since body tissues are chemically different from water, this dose calculation can be subject to errors, particularly due to differences in inelastic nuclear interactions. In recent studies, the authors proposed and validated a PID correction method for these errors. In the present study, the authors used this correction method to assess the influence of these nuclear interactions in body tissues on tumor dose in various clinical cases. Methods: Using 10–20 cases each of prostate, head and neck (HN), bone and soft tissue (BS), lung, liver, pancreas, and uterine neoplasms, the authors first used treatment plans for carbon-ion radiotherapy without nuclear interaction correction to derive uncorrected dose distributions. The authors then compared these distributions with recalculated distributions using the nuclear interaction correction (corrected dose distributions). Results: Median (25%/75% quartiles) differences between the target mean uncorrected doses and corrected doses were 0.2% (0.1%/0.2%), 0.0% (0.0%/0.0%), −0.3% (−0.4%/−0.2%), −0.1% (−0.2%/−0.1%), −0.1% (−0.2%/0.0%), −0.4% (−0.5%/−0.1%), and −0.3% (−0.4%/0.0%) for the prostate, HN, BS, lung, liver, pancreas, and uterine cases, respectively. The largest difference of −1.6% in target mean and −2.5% at maximum were observed in a uterine case. Conclusions: For most clinical cases, dose calculation errors due to the water nonequivalence of the tissues in nuclear interactions would be marginal compared to intrinsic uncertainties in treatment planning, patient setup, beam delivery, and clinical response. In some extreme cases, however, these errors can be substantial. Accordingly, this correction method should be routinely applied to treatment planning in clinical practice.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

SU-D-207B-07: Development of a CT-Radiomics Based Early Response Prediction Model During Delivery of Chemoradiation Therapy for Pancreatic Cancer

Purpose: Pilot study developing a CT-texture based model for early assessment of treatment response during the delivery of chemoradiation therapy (CRT) for pancreatic cancer. Methods: Daily CT data acquired for 24 pancreatic head cancer patients using CT-on-rails, during the routine CT-guided CRT delivery with a radiation dose of 50.4 Gy in 28 fractions, were analyzed. The pancreas head was contoured on each daily CT. Texture analysis was performed within the pancreas head contour using a research tool (IBEX). Over 1300 texture metrics including: grey level co-occurrence, run-length, histogram, neighborhood intensity difference, and geometrical shape features were calculated for each daily CT. Metric-trend information was established by finding the best fit of either a linear, quadratic, or exponential function for each metric value verses accumulated dose. Thus all the daily CT texture information was consolidated into a best-fit trend type for a given patient and texture metric. Linear correlation was performed between the patient histological response vector (good, medium, poor) and all combinations of 23 patient subgroups (statistical jackknife) determining which metrics were most correlated to response and repeatedly reliable across most patients. Control correlations against CT scanner, reconstruction kernel, and gated/nongated CT images were also calculated. Euclidean distance measure was used to group/sort patient vectors based on the data of these trend-response metrics. Results: We found four specific trend-metrics (Gray Level Coocurence Matrix311-1InverseDiffMomentNorm, Gray Level Coocurence Matrix311-1InverseDiffNorm, Gray Level Coocurence Matrix311-1 Homogeneity2, and Intensity Direct Local StdMean) that were highly correlated with patient response and repeatedly reliable. Our four trend-metric model successfully ordered our pilot response dataset (p=0.00070). We found no significant correlation to our control parameters: gating (p=0.7717), scanner (p=0.9741), and kernel (p=0.8586). Conclusion: We have successfully created a CT-texture based early treatment response prediction model using the CTs acquired during the delivery of chemoradiation therapy for pancreatic cancer. Future testing is required to validate the model with more patient data.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

MO-FG-CAMPUS-JeP2-01: 4D-MRI with 3D Radial Sampling and Self-Gating-Based K-Space Sorting: Image Quality Improvement by Slab-Selective Excitation

Purpose: A recent 4D MRI technique based on 3D radial sampling and self-gating-based K-space sorting has shown promising results in characterizing respiratory motion. However due to continuous acquisition and potentially drastic k-space undersampling resultant images could suffer from low blood-to-tissue contrast and streaking artifacts. In this study 3D radial sampling with slab-selective excitation (SS) was proposed in attempt to enhance blood-to-tissue contrast by exploiting the in-flow effect and to suppress the excess signal from the peripheral structures particularly in the superior-inferior direction. The feasibility of improving image quality by using this approach was investigated through a comparison with the previously developed non-selective excitation (NS) approach. Methods: Two excitation approaches SS and NS were compared in 5 cancer patients (1 lung 1 liver 2 pancreas and 1 esophagus) at 3Tesla. Image artifact was assessed in all patients on a 4-point scale (0: poor; 3: excellent). Signal-tonoise ratio (SNR) of the blood vessel (aorta) at the center of field-of-view and its nearby tissue were measured in 3 of the 5 patients (1 liver 2 pancreas) and blood-to-tissue contrast-to-noise ratio (CNR) were then determined. Results: Compared with NS the image quality of SS was visually improved with overall higher signal in all patients (2.6±0.55 vs. 3.4±0.55). SS showed an approximately 2-fold increase of SNR in the blood (aorta: 16.39±1.95 vs. 32.19±7.93) and slight increase in the surrounding tissue (liver/pancreas: 16.91±1.82 vs. 22.31±3.03). As a result the blood-totissue CNR was dramatically higher in the SS method (1.20±1.20 vs. 9.87±6.67). Conclusion: The proposed 3D radial sampling with slabselective excitation allows for reduced image artifact and improved blood SNR and blood-to-tissue CNR. The success of this technique could potentially benefit patients with cancerous tumors that have invaded the surrounding blood vessels where radiation therapy is needed to remove tumor from those regions prior to surgical resection. This work is partially supported by NIH R03CA173273; and CTSI core voucher award.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

TH-EF-BRA-04: Individually Optimized Contrast-Enhanced 4D-CT for Radiotherapy Simulation in Pancreatic Ductal Adenocarcinoma

Purpose: To develop an individually optimized contrast-enhanced (CE) 4D-CT for radiotherapy simulation in pancreatic ductal adenocarcinomas (PDA). Methods: Ten PDA patients were enrolled. Each underwent 3 CT scans: a 4D-CT immediately following a CE 3D-CT and an individually optimized CE 4D-CT using test injection. Three physicians contoured the tumor and pancreatic tissues. We compared image quality scores, tumor volume, motion, tumor-to-pancreas contrast, and contrast-to-noise ratio (CNR) in the 3 CTs. We also evaluated interobserver variations in contouring the tumor using simultaneous truth and performance level estimation (STAPLE). Results: Average image quality scores for CE 3DCT and CE 4D-CT were comparable (4.0 and 3.8, respectively; P=0.47), and both were significantly better than that for 4D-CT (2.6, P<0.001). Tumor-to-pancreas contrast results were comparable in CE 3D-CT and CE 4D-CT (15.5 and 16.7 HU, respectively; P=0.71), and the latter was significantly higher than in 4D-CT (9.2 HU, P=0.03). Image noise in CE 3D-CT (12.5 HU) was significantly lower than in CE 4D-CT (22.1 HU, P<0.001) and 4D-CT (19.4 HU, P=0.005). CNRs were comparable in CE 3D-CT and CE 4DCT (1.4 and 0.8, respectively; P=0.23), and the former was significantly better than in 4D-CT (0.6, P = 0.04). Mean tumor volumes were smaller in CE 3D-CT (29.8 cm{sup 3}) and CE 4D-CT (22.8 cm{sup 3}) than in 4D-CT (42.0 cm{sup 3}), although these differences were not statistically significant. Mean tumor motion was comparable in 4D-CT and CE 4D-CT (7.2 and 6.2 mm, P=0.23). Interobserver variations were comparable in CE 3D-CT and CE 4D-CT (Jaccard index 66.0% and 61.9%, respectively) and were worse for 4D-CT (55.6%) than CE 3D-CT. Conclusion: CE 4D-CT demonstrated characteristics comparable to CE 3D-CT, with high potential for simultaneously delineating the tumor and quantifying tumor motion with a single scan. Supported in part by Philips Healthcare.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2019

In Patients with Localized and Resectable Gastric Cancer, What is the Optimal Extent of Lymph Node Dissection—D1 Versus D2 Versus D3?

Background: Despite advances in the treatment of patients with gastric cancer, the debate over the optimal extent of lymphadenectomy continues. Method: A review of the classification, rationale for, and boundaries of lymphadenectomy is presented. A review of the available literature comparing D1 versus D2 versus D3 lymphadenectomy was performed and included randomized controlled trials, and prospective and retrospective comparative and non-comparative studies. Results: Earlier studies demonstrated increased morbidity with D2 compared with D1 lymphadenectomy, with no significant survival benefit. More recent studies have demonstrated survival benefit of a pancreas and spleen-sparing D2 lymphadenectomy in patients with advanced, node-positive tumors. Para-aortic/D3 dissections contribute to increased morbidity, with no survival benefit. Conclusions: In patients with resectable gastric adenocarcinoma, a D2 lymph node dissection preserving the pancreas and spleen should be considered standard for optimal staging and treatment, provided it is performed by surgeons with sufficient expertise. Extended lymph node dissections beyond D2 should not be routinely performed as it has been shown to have increased morbidity, with no improvement in outcomes. While systemic chemotherapy should be considered standard in patients undergoing D2 lymphadenectomy, the role of adjuvant radiation continues to evolve.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2017

Successful metformin treatment of insulin resistance is associated with down-regulation of the kynurenine pathway

Context: An extensive body of literature indicates a relationship between insulin resistance and the up-regulation of the kynurenine pathway, i.e. the preferential conversion of tryptophan to kynurenine, with subsequent overproduction of diabetogenic downstream metabolites, such as kynurenic acid. Case description: We have measured the concentration of kynurenine pathway metabolites (kynurenines) in the brain and pancreas of two young (27 and 28 yrs) insulin resistant, normoglycemic subjects (M-values 2 and 4 mg/kg/min, respectively) using quantitative C-11-alpha-methyl-tryptophan PET/CT imaging. Both subjects underwent a preventive 12-week metformin treatment regimen (500 mg daily) prior to the PET/CT study. Whereas treatment was successful in one of the subject (M-value increased from 2 to 12 mg/kg/min), response was poor in the other subjects (M-value changed from 4 to 5 mg/kg/min). Brain and pancreas concentrations of kynurenines observed in the responder were similar to that in a healthy control subject, whereas kynurenines determined in the non-responder were about 25% higher and similar to those found in a severely insulin resistant patient. Consistent with this outcome, M-values were negatively correlated with both kynurenic acid levels (R{sup 2} = 0.68, p = 0.09) as well as with the kynurenine to tryptophan ratio (R{sup 2} = 0.63, p = 0.11). Conclusion: The data indicates that kynurenine pathway metabolites are increased in subjects with insulin resistance prior to overt manifestation of hyperglycemia. Moreover, successful metformin treatment leads to a normalization of tryptophan metabolism, most likely as a result of decreased contribution from the kynurenine metabolic pathway.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Structures of two novel crystal forms of Aspergillus oryzae alpha amylase (taka-amylase)

The structures of Aspergillus oryzae α-amylase were determined in a tetragonal crystal, having one molecule as asymmetric unit, and a monoclinic crystal with two molecules as asymmetric unit. Both crystal forms were obtained from trace contaminants of an old commercial lipase preparation. Structures were determined and refined to 1.65 Å and 1.43 Å resolution respectively. The latter crystal has a non-crystallographic (NCS) twofold axis within the asymmetric unit. Glycosylation at Asn197 is evident, and in the tetragonal crystal can be seen to include three, partially disordered sugar residues following the initial N-acetyl glucosamine (NAG). Superposition of the tetragonal crystal model on the α-amylases from Bacillus subtilis (PDB:1BAG), pig pancreas (PDB:3L2L), and barley (PDB:1AMY), show a high degree of coincidence, particularly for the (β/α)8-barrel domains, and especially within the active site. Using this structural agreement between amylases, we extrapolated the binding model of a six residue, limit dextrin found in pig pancreas α-amylase to the A. oryzae enzyme model, which predicts substrate interacting amino acid residues.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2016

Disposition of the Dietary Mutagen 2-Amino-3,8-dimethylimidazo[4,5- f ]quinoxaline in Healthy and Pancreatic Cancer Compromised Humans

Pancreatic cancer is the fourth leading cause of cancer death in the U.S. Once diagnosed, prognosis is poor with a 5-year survival rate of less than 5%. Exposure to carcinogenic heterocyclic amines (HCAs) derived from cooked meat has been shown to be positively associated with pancreatic cancer risk. To evaluate the processes that determines the carcinogenic potential of HCAs for human pancreas, 14-carbon labeled 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a putative human carcinogenic HCA found in well-done cooked meat, was administered at a dietary relevant dose to human volunteers diagnosed with pancreatic cancer undergoing partial pancreatectomy and healthy control volunteers. After 14C-MeIQx exposure, blood and urine was collected for pharmacokinetic and metabolite analysis. MeIQx-DNA adducts levels were quantified by accelerator mass spectrometry from pancreatic tissue excised during surgery from the cancer patient group. Pharmacokinetic analysis of plasma revealed a rapid distribution of MeIQx with a plasma elimination half-life of approximately 3.5 hr in 50% of the cancer patients and all of the control volunteers. In 2 of the 4 cancer patients very low levels of MeIQx were detected in plasma and urine suggesting low absorption from the gut into the plasma. Urinary metabolite analysis revealed five MeIQx metabolites with 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid being the most abundant accounting for 25%–50% of the recovered 14-carbon/ml urine. We found there was no discernable difference in metabolite levels between the cancer patient volunteers and the control group. MeIQx-DNA adduct analysis of pancreas and duodenum tissue revealed adduct levels indistinguishable from background levels. Lastly, although other meat-derived HCA mutagens have been shown to bind DNA in pancreatic tissue, indicating that exposure to HCAs from cooked meat cannot be discounted as a risk factor for pancreatic cancer, the results from this current study show that exposure to a single dietary dose of MeIQx does not readily form measurable DNA adducts under the conditions of the experiment.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2015

N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes

Chromogranin A (ChgA) is an autoantigen for CD4 + T cells in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). The natural ChgA-processed peptide, WE14, is a weak agonist for the prototypical T cell, BDC-2.5, and other ChgA-specific T-cell clones. Mimotope peptides with much higher activity share a C-terminal motif, WXRM(D/E), that is predicted to lie in the p5 to p9 position in the mouse MHC class II, IA g7 binding groove. This motif is also present in WE14 (WSRMD), but at its N terminus. Therefore, to place the WE14 motif into the same position as seen in the mimotopes, we added the amino acids RLGL to its N terminus. Like the other mimotopes, RLGL-WE14, is much more potent than WE14 in T-cell stimulation and activates a diverse population of CD4 + T cells, which also respond to WE14 as well as islets from WT, but not ChgA –/– mice. The crystal structure of the IA g7 –RLGL–WE14 complex confirmed the predicted placement of the peptide within the IA g7 groove. Fluorescent IA g7 –RLGL–WE14 tetramers bind to ChgA-specific T-cell clones and easily detect ChgA-specific T cells in the pancreas and pancreatic lymph nodes of NOD mice. Here, the prediction that many different N-terminal amino acid extensions to the WXRM(D/E) motif are sufficient to greatly improve T-cell stimulation leads us to propose that such a posttranslational modification may occur uniquely in the pancreas or pancreatic lymph nodes, perhaps via the mechanism of transpeptidation. This modification could account for the escape of these T cells from thymic negative selection.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2016

TH-CD-202-03: Enhancing Soft-Tissue CT Contrast for Radiation Therapy Using Mono-Energetic Decompositions of Dual Energy CT

Purpose: It is desirable to increase CT soft-tissue contrast to improve delineation of tumor target and/or surrounding organs at risk (OAR) in RT planning and delivery guidance. The purpose of this work is to investigate the use of monoenergetic decompositions obtained from dual energy (DE) CT to improve soft-tissue contrast. Methods: CT data were acquired for 5 prostate and 5 pancreas patients and a phantom with a CT Scanner (Definition AS Open, Siemens) using both sequential DE protocols and standard protocols. For the DE protocols, the scanner rapidly performs two acquisitions at 80 kVp and 140 kVp. The CT numbers of soft tissue inserts in the phantom (CTED/Gammex) were measured across the spectrum of available monoenergetic decompositions (40 to 140 keV) and compared to the standard protocol (120 kVp, 0.6 pitch, 18 mGy CTDIvol). Contrast, defined as the difference in the average CT number between target and OAR, was measured for all subjects and compared between the DE and standard protocols. Results: Mono-energetic decompositions of the phantom demonstrate an enhancement of soft-tissue contrast as the energy is decreased. For instance, relative to the 120 kVp scans the Liver ED insert increased in CT number by 25 HU while the adipose ED insert decreased by 50 HU. The lowest energy decompositions featured the highest contrast between target and OAR. For every patient, the contrast increased by decomposing at 40 keV. The average increase in contrast relative to a 120 kVp scan for prostate patients at 40 keV was 25.05±17.28 HU while for pancreas patients it was 19.21±17.39 HU. Conclusion: Low energy monoenergetic decompositions from dual-energy CT substantially increase soft-tissue contrast. At the lowest achievable monoenergetic decompositions the maximum soft-tissue contrast is achieved and the delineation of target and OAR is improved. Thus it is beneficial to use DECT in radiation oncology. Supported by Siemens.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Technical Note: Dose effects of 1.5 T transverse magnetic field on tissue interfaces in MRI-guided radiotherapy

Purpose: The integration of MRI with a linear accelerator (MR-linac) offers great potential for high-precision delivery of radiation therapy (RT). However, the electron deflection resulting from the presence of a transverse magnetic field (TMF) can affect the dose distribution, particularly the electron return effect (ERE) at tissue interfaces. The purpose of the study is to investigate the dose effects of ERE at air-tissue and lung-tissue interfaces during intensity-modulated radiation therapy (IMRT) planning. Methods: IMRT and volumetric modulated arc therapy (VMAT) plans for representative pancreas, lung, breast, and head and neck (HN) cases were generated following commonly used clinical dose volume (DV) criteria. In each case, three types of plans were generated: (1) the original plan generated without a TMF; (2) the reconstructed plan generated by recalculating the original plan with the presence of a TMF of 1.5 T (no optimization); and (3) the optimized plan generated by a full optimization with TMF = 1.5 T. These plans were compared using a variety of DV parameters, including V{sub 100%}, D{sub 95%}, DHI [dose heterogeneity index: (D{sub 20%}–D{sub 80%})/D{sub prescription}], D{sub max}, and D{sub 1cc} in OARs (organs at risk) and tissue interface. All the optimizations and calculations in this work were performed on static data. Results: The dose recalculation under TMF showed the presence of the 1.5 T TMF can slightly reduce V{sub 100%} and D{sub 95%} for PTV, with the differences being less than 4% for all but one lung case studied. The TMF results in considerable increases in D{sub max} and D{sub 1cc} on the skin in all cases, mostly between 10% and 35%. The changes in D{sub max} and D{sub 1cc} on air cavity walls are dependent upon site, geometry, and size, with changes ranging up to 15%. The VMAT plans lead to much smaller dose effects from ERE compared to fixed-beam IMRT in pancreas case. When the TMF is considered in the plan optimization, the dose effects of the TMF at tissue interfaces (e.g., air-cavity wall, lung-tissue interfaces, skin) are significantly reduced in most cases. Conclusions: The doses on tissue interfaces can be significantly changed by the presence of a TMF during MR-guided RT when the magnetic field is not included in plan optimization. These changes can be substantially reduced or even eliminated during VMAT/IMRT optimization that specifically considers the TMF, without deteriorating overall plan quality.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2019

How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes

In type 1 diabetes (T1D), proinsulin is a major autoantigen and the insulin B:9-23 peptide contains epitopes for CD4 + T cells in both mice and humans. This peptide requires carboxyl-terminal mutations for uniform binding in the proper position within the mouse IA g7 or human DQ8 major histocompatibility complex (MHC) class II (MHCII) peptide grooves and for strong CD4 + T cell stimulation. In this work, we present crystal structures showing how these mutations control CD4 + T cell receptor (TCR) binding to these MHCII-peptide complexes. Our data reveal stricking similarities between mouse and human CD4 + TCRs in their interactions with these ligands. We also show how fusions between fragments of B:9-23 and of proinsulin C-peptide create chimeric peptides with activities as strong or stronger than the mutated insulin peptides. We propose transpeptidation in the lysosome as a mechanism that could accomplish these fusions in vivo, similar to the creation of fused peptide epitopes for MHCI presentation shown to occur by transpeptidation in the proteasome. Were this mechanism limited to the pancreas and absent in the thymus, it could provide an explanation for how diabetogenic T cells escape negative selection during development but find their modified target antigens in the pancreas to cause T1D.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2019

Radiation and Risk of Liver, Biliary Tract, and Pancreatic Cancers among Atomic Bomb Survivors in Hiroshima and Nagasaki: 1958–2009

The Life Span Study (LSS) of atomic bomb survivors has consistently demonstrated significant excess radiation-related risks of liver cancer since the first cancer incidence report. Here, we present updated information on radiation risks of liver, biliary tract and pancreatic cancers based on 11 additional years of follow-up since the last report, from 1958 to 2009. The current analyses used improved individual radiation doses and accounted for the effects of alcohol consumption, smoking and body mass index. The study participants included 105,444 LSS participants with known individual radiation dose and no known history of cancer at the start of follow-up. Cases were the first primary incident cancers of the liver (including intrahepatic bile duct), biliary tract (gallbladder and other and unspecified parts of biliary tract) or pancreas identified through linkage with population-based cancer registries in Hiroshima and Nagasaki. Poisson regression methods were used to estimate excess relative risks (ERRs) and excess absolute risks (EARs) associated with DS02R1 doses for liver (liver and biliary tract cancers) or pancreas (pancreatic cancer). We identified 2,016 incident liver cancer cases during the follow-up period. Radiation dose was significantly associated with liver cancer risk (ERR per Gy: 0.53, 95% CI: 0.23 to 0.89; EAR per 10,000 person-year Gy: 5.32, 95% CI: 2.49 to 8.51). There was no evidence for curvature in the radiation dose response (P=0.344). ERRs by age-at-exposure categories were significantly increased among those who were exposed at 0–9, 10–19 and 20–29 years, but not significantly increased after age 30 years, although there was no statistical evidence of heterogeneity in these ERRs (P = 0.378). The radiation ERRs were not affected by adjustment for smoking, alcohol consumption or body mass index. As in previously reported studies, radiation dose was not associated with risk of biliary tract cancer (ERR per Gy: –0.02, 95% CI: –0.25 to 0.30). Radiation dose was associated with a nonsignificant increase in pancreatic cancer risk (ERR per Gy: 0.38, 95% CI: <0 to 0.83). The increased risk was statistically significant among women (ERR per Gy: 0.70, 95% CI: 0.12 to 1.45), but not among men.

60 APPLIED LIFE SCIENCES↗

NASA NTRS2000

Increased Arginine and Ornithine Flux in Islets of Langerhans Cultured in a Microgravity Model System

Microgravity is associated with alterations in protein metabolism of both muscle and bone. That pancreas-derived insulin is essential to the normal maintenance of body protein balance is well known. The importance of altered endocrine pancreas function in microgravity is not yet established. We proposed to examine the influence of a microgravity model system, the High Aspect Ratio Vessel (HARV) upon islets of Langerhans from Wistar Furth rats. Islets were cultured in the HARV for 48 hr in Medium-199 and contrasted to static control islets (PLATE). Nitrogenous compounds elaborated into the media (micromoles/ml) were analyzed at 0 and 48 hr of culture and compared to PLATE with a 2-way ANOVA (HARV vs Hour).

Tobin, B. W.↗

NASA NTRS2002

Insulin secretion and sensitivity in space flight: diabetogenic effects

Nearly three decades of space flight research have suggested that there are subclinical diabetogenic changes that occur in microgravity. Alterations in insulin secretion, insulin sensitivity, glucose tolerance, and metabolism of protein and amino acids support the hypothesis that insulin plays an essential role in the maintenance of muscle mass in extended-duration space flight. Experiments in flight and after flight and ground-based bedrest studies have associated microgravity and its experimental paradigms with manifestations similar to those of diabetes, physical inactivity, and aging. We propose that these manifestations are characterized best by an etiology that falls into the clinical category of "other" causes of diabetes, including, but not restricted to, genetic beta-cell defects, insulin action defects, diseases of the endocrine pancreas, endocrinopathies, drug or chemically induced diabetes, infections, immune-mediated metabolic alteration, and a host of genetic related diseases. We present data showing alterations in tumor necrosis factor-alpha production, insulin secretion, and amino acid metabolism in pancreatic islets of Langerhans cultured in a ground-based cell culture bioreactor that mimics some of the effects of microgravity. Taken together, space flight research, ground-based studies, and bioreactor studies of pancreatic islets of Langerhans support the hypothesis that the pancreas is unable to overcome peripheral insulin resistance and amino acid dysregulation during space flight. We propose that measures of insulin secretion and insulin action will be necessary to design effective countermeasures against muscle loss, and we advance the "disposition index" as an essential model to be used in the clinical management of space flight-induced muscle loss.

Review↗

NASA NTRS1996

Calbindins decreased after space flight

Exposure of the body to microgravity during space flight causes a series of well-documented changes in Ca2+ metabolism, yet the cellular and molecular mechanisms leading to these changes are poorly understood. Calbindins, vitamin D-dependent Ca2+ binding proteins, are believed to have a significant role in maintaining cellular Ca2+ homeostasis. In this study, we used biochemical and immunocytochemical approaches to analyze the expression of calbindin-D28k and calbindin-D9k in kidneys, small intestine, and pancreas of rats flown for 9 d aboard the space shuttle. The effects of microgravity on calbindins in rats from space were compared with synchronous Animal Enclosure Module controls, modeled weightlessness animals (tail suspension), and their controls. Exposure to microgravity resulted in a significant and sustained decrease in calbindin-D28k content in the kidney and calbindin-D9k in the small intestine of flight animals, as measured by enzyme-linked immunosorbent assay (ELISA). Modeled weightlessness animals exhibited a similar decrease in calbindins by ELISA. Immunocytochemistry (ICC) in combination with quantitative computer image analysis was used to measure in situ the expression of calbindins in the kidney and the small intestine, and the expression of insulin in pancreas. There was a large decrease of immunoreactivity in renal distal tubular cell-associated calbindin-D28k and in intestinal absorptive cell-associated calbindin-D9k of space flight and modeled weightlessness animals compared with matched controls. No consistent difference in pancreatic insulin immunoreactivity between space flight, modeled weightlessness, and controls was observed. Regression analysis of results obtained by quantitative ICC and ELISA for space flight, modeled weightlessness animals, and their controls demonstrated a significant correlation. These findings after a short-term exposure to microgravity or modeled weightlessness suggest that a decreased expression of calbindins may contribute to the disorders of Ca2+ metabolism induced by space flight.

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