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DOE OSTI2015

In vitro biotransformation of tris(2-butoxyethyl) phosphate (TBOEP) in human liver and serum

Tris(2-butoxyethyl) phosphate (TBOEP) is a plasticizer present in indoor dust, reaching levels of several micrograms per gram. Such levels could lead to significant daily exposure of adults and children. Currently, no toxicokinetic data are available to estimate TBOEP clearance in humans after uptake and therefore, one objective of this study was to investigate intrinsic clearance of TBOEP by human liver microsome (HLM) and serum enzymes. Another objective was to generate information to identify and prioritize several metabolites of TBOEP for investigation of human exposure by biomonitoring. 1D and 2D-NMR methodologies were successfully applied on a mixture of the metabolites to confirm the structure of 3-HO-TBOEP (bis(2-butoxyethyl) 3-hydroxyl-2-butoxyethyl phosphate) and to tentatively assign structures to 1-HO-TBOEP and 2-HO-TBOEP. HO-TBOEP isomers and bis(2-butoxyethyl) phosphate (BBOEP), bis(2-butoxyethyl) hydroxyethyl phosphate (BBOEHEP) were further monitored by liquid chromatography–tandem mass spectrometry. Rates of formation of BBOEHEP and HO-TBOEP metabolites by liver enzymes were best described by the Michaelis–Menten model. Apparent K{sub m} values for BBOEHEP, 3-HO-TBOEP, and sum of 1- and 2-HO-TBOEP isomer formation were 152, 197 and 148 μM, respectively. Apparent V{sub max} values for the formation of BBOEHEP, 3-HO-TBOEP, and the sum of 1- and 2-HO-TBOEP isomers were 2560, 643, and 254 pmol/min/mg protein, respectively. No detectable formation of BBOEP occurred with liver or serum enzymes. Our findings indicate that intrinsic clearance of TBOEP is mainly catalyzed by oxidative enzymes in the liver and that its major in vitro metabolite is BBOEHEP. These findings can be applied in human biomonitoring studies and risk assessment. - Highlights: • First steps in the elucidation of TBOEP toxicokinetics • Quantification of TBOEP metabolites in human serum and liver microsomes • No detectable formation of BBOEP occurred with liver or serum enzymes. • Oxidative dealkylation to BBOEHEP was likely the major metabolic pathway. • 1D-NMR and 2D-NMR were used to tentatively assign structures of HO-TBOEP isomers.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Distribution, lipid-bilayer affinity and kinetics of the metabolic effects of dinoseb in the liver

Dinoseb is a highly toxic pesticide of the dinitrophenol group. Its use has been restricted, but it can still be found in soils and waters in addition to being a component of related pesticides that, after ingestion by humans or animals, can originate the compound by enzymatic hydrolysis. As most dinitrophenols, dinoseb uncouples oxidative phosphorylation. In this study, distribution, lipid bilayer affinity and kinetics of the metabolic effects of dinoseb were investigated, using mainly the isolated perfused rat liver, but also isolated mitochondria and molecular dynamics simulations. Dinoseb presented high affinity for the hydrophobic region of the lipid bilayers, with a partition coefficient of 3.75 × 10{sup 4} between the hydrophobic and hydrophilic phases. Due to this high affinity for the cellular membranes dinoseb underwent flow-limited distribution in the liver. Transformation was slow but uptake into the liver space was very pronounced. For an extracellular concentration of 10 μM, the equilibrium intracellular concentration was equal to 438.7 μM. In general dinoseb stimulated catabolism and inhibited anabolism. Half-maximal stimulation of oxygen uptake in the whole liver occurred at concentrations (2.8–5.8 μM) at least ten times above those in isolated mitochondria (0.28 μM). Gluconeogenesis and ureagenesis were half-maximally inhibited at concentrations between 3.04 and 5.97 μM. The ATP levels were diminished, but differently in livers from fed and fasted rats. Dinoseb disrupts metabolism in a complex way at concentrations well above its uncoupling action in isolated mitochondria, but still at concentrations that are low enough to be dangerous to animals and humans even at sub-lethal doses. - Highlights: • Dinoseb presents high affinity for the hydrophobic region of the lipid bilayers. • Its cellular concentration may exceed the extracellular one by a factor of 43.9. • One order of magnitude separates the active concentrations in mitochondria and liver. • Hepatic metabolism is disrupted in the concentration range up to 10 μM.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

SU-E-I-87: Automated Liver Segmentation Method for CBCT Dataset by Combining Sparse Shape Composition and Probabilistic Atlas Construction

Purpose: The aiming of this study was to extract liver structures for daily Cone beam CT (CBCT) images automatically. Methods: Datasets were collected from 50 intravenous contrast planning CT images, which were regarded as training dataset for probabilistic atlas and shape prior model construction. Firstly, probabilistic atlas and shape prior model based on sparse shape composition (SSC) were constructed by iterative deformable registration. Secondly, the artifacts and noise were removed from the daily CBCT image by an edge-preserving filtering using total variation with L1 norm (TV-L1). Furthermore, the initial liver region was obtained by registering the incoming CBCT image with the atlas utilizing edge-preserving deformable registration with multi-scale strategy, and then the initial liver region was converted to surface meshing which was registered with the shape model where the major variation of specific patient was modeled by sparse vectors. At the last stage, the shape and intensity information were incorporated into joint probabilistic model, and finally the liver structure was extracted by maximum a posteriori segmentation.Regarding the construction process, firstly the manually segmented contours were converted into meshes, and then arbitrary patient data was chosen as reference image to register with the rest of training datasets by deformable registration algorithm for constructing probabilistic atlas and prior shape model. To improve the efficiency of proposed method, the initial probabilistic atlas was used as reference image to register with other patient data for iterative construction for removing bias caused by arbitrary selection. Results: The experiment validated the accuracy of the segmentation results quantitatively by comparing with the manually ones. The volumetric overlap percentage between the automatically generated liver contours and the ground truth were on an average 88%–95% for CBCT images. Conclusion: The experiment demonstrated that liver structures of CBCT with artifacts can be extracted accurately for following adaptive radiation therapy. This work is supported by National Natural Science Foundation of China (No. 61201441), Research Fund for Excellent Young and Middle-aged Scientists of Shandong Province (No. BS2012DX038), Project of Shandong Province Higher Educational Science and Technology Program (No. J12LN23), Jinan youth science and technology star (No.20120109)

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

Assessing and accounting for the impact of respiratory motion on FDG uptake and viable volume for liver lesions in free-breathing PET using respiration-suspended PET images as reference

Purpose: To assess and account for the impact of respiratory motion on the variability of activity and volume determination of liver tumor in positron emission tomography (PET) through a comparison between free-breathing (FB) and respiration-suspended (RS) PET images. Methods: As part of a PET/computed tomography (CT) guided percutaneous liver ablation procedure performed on a PET/CT scanner, a patient's breathing is suspended on a ventilator, allowing the acquisition of a near-motionless PET and CT reference images of the liver. In this study, baseline RS and FB PET/CT images of 20 patients undergoing thermal ablation were acquired. The RS PET provides near-motionless reference in a human study, and thereby allows a quantitative evaluation of the effect of respiratory motion on PET images obtained under FB conditions. Two methods were applied to calculate tumor activity and volume: (1) threshold-based segmentation (TBS), estimating the total lesion glycolysis (TLG) and the segmented volume and (2) histogram-based estimation (HBE), yielding the background-subtracted lesion (BSL) activity and associated volume. The TBS method employs 50% of the maximum standardized uptake value (SUV{sub max}) as the threshold for tumors with SUV{sub max} ≥ 2× SUV{sub liver-bkg}, and tumor activity above this threshold yields TLG{sub 50%}. The HBE method determines local PET background based on a Gaussian fit of the low SUV peak in a SUV-volume histogram, which is generated within a user-defined and optimized volume of interest containing both local background and lesion uptakes. Voxels with PET intensity above the fitted background were considered to have originated from the tumor and used to calculate the BSL activity and its associated lesion volume. Results: Respiratory motion caused SUV{sub max} to decrease from RS to FB by −15% ± 11% (p = 0.01). Using TBS method, there was also a decrease in SUV{sub mean} (−18% ± 9%, p = 0.01), but an increase in TLG{sub 50%} (18% ± 36%) and in the segmented volume (47% ± 52%, p = 0.01) from RS to FB PET images. The background uptake in normal liver was stable, 1% ± 9%. In contrast, using the HBE method, the differences in both BSL activity and BSL volume from RS to FB were −8% ± 10% (p = 0.005) and 0% ± 16% (p = 0.94), respectively. Conclusions: This is the first time that almost motion-free PET images of the human liver were acquired and compared to free-breathing PET. The BSL method's results are more consistent, for the calculation of both tumor activity and volume in RS and FB PET images, than those using conventional TBS. This suggests that the BSL method might be less sensitive to motion blurring and provides an improved estimation of tumor activity and volume in the presence of respiratory motion.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Position tracking of moving liver lesion based on real-time registration between 2D ultrasound and 3D preoperative images

Purpose: Registration between 2D ultrasound (US) and 3D preoperative magnetic resonance (MR) (or computed tomography, CT) images has been studied recently for US-guided intervention. However, the existing techniques have some limits, either in the registration speed or the performance. The purpose of this work is to develop a real-time and fully automatic registration system between two intermodal images of the liver, and subsequently an indirect lesion positioning/tracking algorithm based on the registration result, for image-guided interventions. Methods: The proposed position tracking system consists of three stages. In the preoperative stage, the authors acquire several 3D preoperative MR (or CT) images at different respiratory phases. Based on the transformations obtained from nonrigid registration of the acquired 3D images, they then generate a 4D preoperative image along the respiratory phase. In the intraoperative preparatory stage, they properly attach a 3D US transducer to the patient’s body and fix its pose using a holding mechanism. They then acquire a couple of respiratory-controlled 3D US images. Via the rigid registration of these US images to the 3D preoperative images in the 4D image, the pose information of the fixed-pose 3D US transducer is determined with respect to the preoperative image coordinates. As feature(s) to use for the rigid registration, they may choose either internal liver vessels or the inferior vena cava. Since the latter is especially useful in patients with a diffuse liver disease, the authors newly propose using it. In the intraoperative real-time stage, they acquire 2D US images in real-time from the fixed-pose transducer. For each US image, they select candidates for its corresponding 2D preoperative slice from the 4D preoperative MR (or CT) image, based on the predetermined pose information of the transducer. The correct corresponding image is then found among those candidates via real-time 2D registration based on a gradient-based similarity measure. Finally, if needed, they obtain the position information of the liver lesion using the 3D preoperative image to which the registered 2D preoperative slice belongs. Results: The proposed method was applied to 23 clinical datasets and quantitative evaluations were conducted. With the exception of one clinical dataset that included US images of extremely low quality, 22 datasets of various liver status were successfully applied in the evaluation. Experimental results showed that the registration error between the anatomical features of US and preoperative MR images is less than 3 mm on average. The lesion tracking error was also found to be less than 5 mm at maximum. Conclusions: A new system has been proposed for real-time registration between 2D US and successive multiple 3D preoperative MR/CT images of the liver and was applied for indirect lesion tracking for image-guided intervention. The system is fully automatic and robust even with images that had low quality due to patient status. Through visual examinations and quantitative evaluations, it was verified that the proposed system can provide high lesion tracking accuracy as well as high registration accuracy, at performance levels which were acceptable for various clinical applications.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

SU-E-J-165: Dosimetric Impact of Liver Rotations in Stereotactic Body Radiation Therapy

Purpose: Often in liver stereotactic body radiotherapy a single fiducial is implanted near the tumor for image-guided treatment delivery. In such cases, rotational corrections are calculated based on the spine. This study quantifies rotational differences between the spine and liver, and investigates the corresponding dosimetric impact. Methods: Seven patients with 3 intrahepatic fiducials and 4DCT scans were identified. The planning CT was separately co-registered with 4 phases of the 4DCT (0%, 50%, 100% inhale and 50% exhale) by 1) rigid registration of the spine, and 2) point-based registration of the 3 fiducials. Rotation vectors were calculated for each registration. Translational differences in fiducial positions between the 2 registrations methods were investigated. Dosimetric impact due to liver rotations and deformations was assessed using critical structures delineated on the 4DCT phases. For dose comparisons, a single fiducial was translationally aligned following spine alignment to represent what is typically done in the clinic. Results: On average, differences between spine and liver rotations during the 0%, 50%, 100% inhale, and 50% exhale phases were 3.23°, 3.27°, 2.26° and 3.11° (pitch), 3.00°, 2.24°, 3.12° and 1.73° (roll), and 1.57°, 1.98°, 2.09° and 1.36° (yaw), respectively. The maximum difference in rotations was 12°, with differences of >3° seen in 14/28 (pitch), 10/28 (roll), and 6/28 (yaw) cases. Average fiducial displacements of 2.73 (craniocaudal), 1.04 (lateral) and 1.82 mm (vertical) were seen. Evaluating percent dose differences for 5 patients at the peaks of the respiratory cycle, the maximum dose to the duodenum, stomach, bowel and esophagus differed on average by 11.4%, 5.3%, 11.2% and 49.1% between the 2 registration methods. Conclusion: Lack of accounting for liver rotation during treatment might Result in clinically significant dose differences to critical structures. Both rotational and translational deviations should be considered in planning margins when using spine alignment for liver treatments.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

SU-E-J-260: Quantitative Image Feature Analysis of Multiphase Liver CT for Hepatocellular Carcinoma (HCC) in Radiation Therapy

Purpose: To identify the effective quantitative image features (radiomics features) for prediction of response, survival, recurrence and metastasis of hepatocellular carcinoma (HCC) in radiotherapy. Methods: Multiphase contrast enhanced liver CT images were acquired in 16 patients with HCC on pre and post radiation therapy (RT). In this study, arterial phase CT images were selected to analyze the effectiveness of image features for the prediction of treatment outcome of HCC to RT. Response evaluated by RECIST criteria, survival, local recurrence (LR), distant metastasis (DM) and liver metastasis (LM) were examined. A radiation oncologist manually delineated the tumor and normal liver on pre and post CT scans, respectively. Quantitative image features were extracted to characterize the intensity distribution (n=8), spatial patterns (texture, n=36), and shape (n=16) of the tumor and liver, respectively. Moreover, differences between pre and post image features were calculated (n=120). A total of 360 features were extracted and then analyzed by unpaired student’s t-test to rank the effectiveness of features for the prediction of response. Results: The five most effective features were selected for prediction of each outcome. Significant predictors for tumor response and survival are changes in tumor shape (Second Major Axes Length, p= 0.002; Eccentricity, p=0.0002), for LR, liver texture (Standard Deviation (SD) of High Grey Level Run Emphasis and SD of Entropy, both p=0.005) on pre and post CT images, for DM, tumor texture (SD of Entropy, p=0.01) on pre CT image and for LM, liver (Mean of Cluster Shade, p=0.004) and tumor texture (SD of Entropy, p=0.006) on pre CT image. Intensity distribution features were not significant (p>0.09). Conclusion: Quantitative CT image features were found to be potential predictors of the five endpoints of HCC in RT. This work was supported in part by the National Cancer Institute Grant R01CA172638.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

SU-E-T-300: Dosimetric Comparision of 4D Radiation Therapy and 3D Radiation Therapy for the Liver Tumor Based On 4D Medical Image

Purpose: The purpose of this work was to determine the dosimetric benefit to normal tissues by tracking liver tumor dose in four dimensional radiation therapy (4DRT) on ten phases of four dimensional computer tomagraphy(4DCT) images. Methods: Target tracking each phase with the beam aperture for ten liver cancer patients were converted to cumulative plan and compared to the 3D plan with a merged target volume based on 4DCT image in radiation treatment planning system (TPS). The change in normal tissue dose was evaluated in the plan by using the parameters V5, V10, V15, V20,V25, V30, V35 and V40 (volumes receiving 5, 10, 15, 20, 25, 30, 35 and 40Gy, respectively) in the dose-volume histogram for the liver; mean dose for the following structures: liver, left kidney and right kidney; and maximum dose for the following structures: bowel, duodenum, esophagus, stomach and heart. Results: There was significant difference between 4D PTV(average 115.71cm3 )and ITV(169.86 cm3). When the planning objective is 95% volume of PTV covered by the prescription dose, the mean dose for the liver, left kidney and right kidney have an average decrease 23.13%, 49.51%, and 54.38%, respectively. The maximum dose for bowel, duodenum,esophagus, stomach and heart have an average decrease 16.77%, 28.07%, 24.28%, 4.89%, and 4.45%, respectively. Compared to 3D RT, radiation volume for the liver V5, V10, V15, V20, V25, V30, V35 and V40 by using the 4D plans have a significant decrease(P≤0.05). Conclusion: The 4D plan method creates plans that permit better sparing of the normal structures than the commonly used ITV method, which delivers the same dosimetric effects to the target.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

Technical Note: Validation and implementation of a wireless transponder tracking system for gated stereotactic ablative radiotherapy of the liver

Purpose: Tracking soft-tissue targets has recently been cleared as a new application of Calypso, an electromagnetic wireless transponder tracking system, allowing for gated treatment of the liver based on the motion of the target volume itself. The purpose of this study is to describe the details of validating the Calypso system for wireless transponder tracking of the liver and to present the clinical workflow for using it to deliver gated stereotactic ablative radiotherapy (SABR). Methods: A commercial 3D diode array motion system was used to evaluate the dynamic tracking accuracy of Calypso when tracking continuous large amplitude motion. It was then used to perform end-to-end tests to evaluate the dosimetric accuracy of gated beam delivery for liver SABR. In addition, gating limits were investigated to determine how large the gating window can be while still maintaining dosimetric accuracy. The gating latency of the Calypso system was also measured using a customized motion phantom. Results: The average absolute difference between the measured and expected positional offset was 0.3 mm. The 2%/2 mm gamma pass rates for the gated treatment delivery were greater than 97%. When increasing the gating limits beyond the known extent of planned motion, the gamma pass rates decreased as expected. The 2%/2 mm gamma pass rate for a 1, 2, and 3 mm increase in gating limits was measured to be 97.8%, 82.9%, and 61.4%, respectively. The average gating latency was measured to be 63.8 ms for beam-hold and 195.8 ms for beam-on. Four liver patients with 17 total fractions have been successfully treated at our institution. Conclusions: Wireless transponder tracking was validated as a dosimetrically accurate way to provide gated SABR of the liver. The dynamic tracking accuracy of the Calypso system met manufacturer’s specification, even for continuous large amplitude motion that can be encountered when tracking liver tumors close to the diaphragm. The measured beam-hold gating latency was appropriate for targets that will traverse the gating limit each respiratory cycle causing the beam to be interrupted constantly throughout treatment delivery.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2019

Laparoscopic Isolated Total Caudate Lobectomy for Hepatocellular Carcinoma Located in the Paracaval Portion of the Cirrhotic Liver

Background: Despite the widespread use of laparoscopic hepatectomies in past decades, laparoscopic isolated total caudate lobectomy for hepatocellular carcinoma (HCC) remains challenging,{sup 1,2} especially for patients with cirrhosis. Moreover, a laparoscopic isolated total caudate lobectomy for HCC originating in the paracaval portion of the caudate lobe is very rare. We herein present a video showing laparoscopic total caudate lobectomy for a cirrhotic patient with HCC located in the paracaval portion of the caudate lobe. Methods: A 58-year-old woman who suffered from hepatitis C virus-related cirrhosis was admitted to our institution. The preoperative computed tomography showed a 2.5 × 2.0 cm liver mass located in segment I that was very close to the right hepatic pedicle. Although her liver function was Child–Pugh A, the indocyanine green (ICG)-15 test was high at 10.9%. Right hepatectomy plus caudate lobectomy was not adopted because of the severe cirrhosis and the elevated ICG-15. Thus, laparoscopic isolated total caudate lobectomy was contemplated. Results: The patient was placed in the supine position. After full mobilization, the caudate lobe was exposed. The third porta of the liver was then dissected and the short hepatic veins were controlled with clips and LigaSure. The dissection was finished when the whole third porta of the liver was freed. Subsequently, the portal branches to the caudate lobe were ligated and cut. The combination between the left- and right-sided laparoscopic approaches was used to transect liver parenchyma. The superficial parenchyma was divided using an harmonic scalpel, while the deeper tissue was divided using a Cavitron ultrasonic aspirator (CUSA). The Pringle maneuver was used intermittently during the parenchymal transection as necessary. In the left-sided approach, the caudate lobe was resected along the left and middle hepatic vein toward the right side, to expose the dorsal semicircle of the right hepatic vein. In the right-sided approach, the resection started from the right border of the process portion to the root of the right hepatic vein in the cranial direction. Finally, the whole caudate lobe was resected and the three main hepatic veins were exposed on the cutting plane. The specimen was removed from suprapubic incision. The operative time was 300 min and the total Pringle time was 50 min. The postoperative course was uneventful. Conclusions: A laparoscopic isolated total caudate lobectomy for HCC located in the paracaval portion of the cirrhotic liver seems to be feasible and safe in selected patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2021

Biophysical characterization and a roadmap towards the NMR solution structure of G0S2, a key enzyme in non-alcoholic fatty liver disease

In the United States non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, affecting an estimated 80 to 100 million people. It occurs in every age group, but predominantly in people with risk factors such as obesity and type 2 diabetes. NAFLD is marked by fat accumulation in the liver leading to liver inflammation, which may lead to scarring and irreversible damage progressing to cirrhosis and liver failure. In animal models, genetic ablation of the protein G0S2 leads to alleviation of liver damage and insulin resistance in high fat diets. The research presented in this paper aims to aid in rational based drug design for the treatment of NAFLD by providing a pathway for a solution state NMR structure of G0S2. Here we describe the expression of G0S2 in an E. coli system from two different constructs, both of which are confirmed to be functionally active based on the ability to inhibit the activity of Adipose Triglyceride Lipase. In one of the constructs, preliminary NMR spectroscopy measurements show dominant alpha-helical characteristics as well as resonance assignments on the N-terminus of G0S2, allowing for further NMR work with this protein. Additionally, the characterization of G0S2 oligomers are outlined for both constructs, suggesting that G0S2 may defensively exist in a multimeric state to protect and potentially stabilize the small 104 amino acid protein within the cell. This information presented on the structure of G0S2 will further guide future development in the therapy for NAFLD.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Toward Revealing Microcystin Distribution in Mouse Liver Tissue Using MALDI-MS Imaging

Cyanotoxins can be found in water and air during cyanobacterial harmful algal blooms (cHABs) in lakes and rivers. Therefore, it is very important to monitor their potential uptake by animals and humans as well as their health effects and distribution in affected organs. Herein, the distribution of hepatotoxic peptide microcystin-LR (MC-LR) is investigated in liver tissues of mice gavaged with this most common MC congener. Preliminary matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) imaging experiments performed using a non-automated MALDI matrix deposition device and a MALDI-time-of-flight (TOF) mass spectrometer yielded ambiguous results in terms of MC-LR distribution in liver samples obtained from MC-LR-gavaged mice. The tissue preparation for MALDI-MS imaging was improved by using an automated sprayer for matrix deposition, and liver sections were imaged using an Nd:YAG MALDI laser coupled to a 15 Tesla Fourier-transform ion cyclotron resonance (FT-ICR)-mass spectrometer. MALDI-FT-ICR-MS imaging provided unambiguous detection of protonated MC-LR (calculated m/z 995.5560, z = +1) and the sodium adduct of MC-LR (m/z 1017.5380, z = +1) in liver sections from gavaged mice with great mass accuracy and ultra-high mass resolution. Since both covalently bound and free MC-LR can be found in liver of mice exposed to this toxin, the present results indicate that the distribution of free microcystins in tissue sections from affected organs, such as liver, can be monitored with high-resolution MALDI-MS imaging.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Misclassification of primary liver cancer in the Life Span Study of atomic bomb survivors

Primary liver cancer is difficult to diagnose accurately at death, due to metastases from nearby organs and to concomitant diseases, such as chronic hepatitis and cirrhosis. Trends in diagnostic accuracy could affect radiation risk estimates for incident liver cancer by altering background rates or by impacting risk modification by sex and age. We quantified the potential impact of death‐certificate inaccuracies on radiation risk estimates for liver cancer in the Life Span Study of atomic bomb survivors. True‐positive and false‐negative rates were obtained from a previous study that compared death‐certificate causes of death with those based on pathological review, from 1958 to 1987. We assumed various scenarios for misclassification rates after 1987. We obtained estimated true positives and estimated false negatives by stratified sampling from binomial distributions with probabilities given by the true‐positive and false‐negative rates, respectively. Poisson regression methods were applied to highly stratified person‐year tables of corrected case counts and accrued person years. During the study period (1958–2009), there were 1,885 cases of liver cancer, which included 383 death‐certificate‐only (DCO) cases; 1,283 cases with chronic liver disease as the underlying cause of death; and 150 DCO cases of pancreatic cancer among 105,444 study participants. Across the range of scenarios considered, radiation risk estimates based on corrected case counts were attenuated, on average, by 13–30%. Our results indicated that radiation risk estimates for liver cancer were potentially sensitive to death‐certificate inaccuracies. Additional data are needed to inform misclassification rates in recent years.

French, Benjamin↗

DOE OSTI2016

Metabolic Changes Underlying Interactions Between Obesity and Non‐Alcoholic Fatty Liver Disease in South Asian Adults

Non‐alcoholic fatty liver disease (NAFLD) is often referred to as the hepatic manifestation of the metabolic syndrome, which is characterized by at least three of the following: hypertension, hyperglycemia, abdominal obesity, elevated plasma triglycerides and reduced plasma high‐density lipoproteins. While hepatic steatosis has been well studied in animal models, the relationship between body weight, hepatic steatosis and insulin resistance is not well characterized in humans. Moreover, not all human subjects with obesity develop metabolic complications. In addition, it is unclear why South Asian adults develop insulin resistance and diabetes even at lower levels of adiposity and body mass index compared to their Western counterparts. To address this question, we used a convenient sample of Sri Lankan adult females (n = 30) who underwent routine abdominal surgery at the Teaching Hospital of Peradeniya. Anthropometric data, adipose tissue specimens and fasted serum samples were collected for analyses of glucose, lipid and inflammatory markers. Histological sections of adipose tissue were obtained from omental fat (OF) and anterior abdominal wall fat (AF), and adipocyte cross‐sectional area was measured using the ImageJ software. Further, the presence of hepatic steatosis was assessed using ultrasound scanning by a radiologist. Participants with higher grade of fatty liver had a significantly higher body mass index (BMI), fasting blood glucose and aspartate aminotransferase levels. Additionally, participants with higher grade of fatty liver also had significantly higher serum levels of non‐HDL cholesterol and the pro‐inflammatory adipokine, resistin. Interestingly, there were no significant differences in serum adiponectin levels between the groups. Individuals with fatty liver also had a higher mean adipocyte area in both OF and AF, indicating a higher degree of adipocyte hypertrophy associated with fatty liver. Currently, the measurements of additional biomarkers of inflammation and insulin resistance are underway. These findings indicate distinct metabolic differences between South Asian adults with varying degrees of fatty liver, and may help in establishing effective treatment strategies for obesity‐associated NAFLD. Support or Funding Information Funded by an International Research/Development Seed grant from the Office of International Affairs and the Office of the Vice President for Research at Texas Tech university (TTU), and an International Research Seed Grant from The College of Human Sciences at TTU, and by the International Research Center, University of Peradeniya.

Albracht‐Schulte, Kembra↗

DOE OSTI2014

Severity of liver disease affects HCV kinetics in patients treated with intravenous silibinin monotherapy

HCV kinetic analysis and modeling during antiviral therapy have not been performed in decompensated cirrhotic patients awaiting liver transplantation. Here, viral and host parameters were compared in patients treated with daily intravenous silibinin (SIL) monotherapy for 7 days according to the severity of their liver disease. Data were obtained from 25 patients, 12 non-cirrhotic, 8 with compensated cirrhosis and 5 with decompensated cirrhosis. The standard-biphasic model with time-varying SIL effectiveness (from 0 to ε max ) was fit to viral kinetic data. Our results show that baseline viral load and age were significantly associated with the severity of liver disease (p<0.0001). A biphasic viral decline was observed in most patients with a higher first phase decline patients with less severe liver disease. The maximal effectiveness, ε max , was significantly (p≤0.032) associated with increasing severity of liver disease (ε max [s.e.]=0.86[0.05], ε max =0.69[0.06] and ε max =0.59[0.1]). The 2nd phase decline slope was not significantly different among groups (mean 1.88±0.15 log 10 IU/ml/wk, p=0.75) as was the rate of change of SIL effectiveness (k=2.12/day[standard error, SE=0.18/day]). HCV-infected cell loss rate (δ[SE]=0.62/day[0.05/day]) was high and similar among groups. We conclude that the high loss rate of HCV-infected cells suggests that sufficient dose and duration of SIL might achieve viral suppression in advanced liver disease.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRSDate not supplied

Comparison of Radiation-induced Damage Between Livers from Control and Chimeric Mice

Assessment of human health risks associated with space radiation exposure is based largely on the knowledge learned from studies in which animals, mostly rodents, are exposed to high-LET radiation on the ground. It has been recognized that translation of animal results to meaningful implications for human disease can be challenging, particularly for certain risk categories such as the high-LET radiation effects in the central nervous system (CNS). Considering limitations in utilizing non-human primates and clinical studies in humans, chimeric animals can potentially bridge the knowledge gap between rodents and humans. In a chimeric animal, a specific organ or a cell type is replaced with respective human cells that are functional. In this pilot study, we use PXB mice whose livers contain >90% human cells. These mice are exposed to gamma rays for investigations of DNA damage and transcriptomics changes in the humanized livers. Results obtained from PXB mice were compared non-engrafted control animals from the same background strain that are exposed to identical conditions. Staining of the liver tissues with H&E indicated that the human liver tissue in chimeric mice responds differently than the mouse liver tissue to gamma radiation on the cellular level, as evidenced by differences in inflammation and cellular damage seen on histopathology. The gene expression data collected from the liver samples will also be presented, which potentially offers an explanation for the differential responses.

Honglu Wu↗

NASA NTRSDate not supplied

Comparison of Radiation-Induced Damage Between Livers From Control and Chimeric Mice

Assessment of human health risks associated with space radiation exposure is based largely on the knowledge gained from studies in which animals, mostly rodents, are exposed to high-LET radiation on the ground. It has been recognized that translation of animal results to meaningful implications for human disease can be challenging, particularly for certain risk categories such as the high-LET radiation effects in the central nervous system (CNS). Considering limitations in utilizing non-human primates and clinical studies in humans, chimeric animals can potentially bridge the knowledge gap between rodents and humans. In a chimeric animal, a specific organ or a cell type is replaced with respective human cells that are functional. In this pilot study, we used PXB mice whose livers contain >90% human cells. These mice were exposed to gamma rays to investigate DNA damage and transcriptomics changes in the chimeric livers. Results obtained from PXB mice were compared to non-engrafted control animals from the same background strain that were exposed to identical conditions. Staining of the liver tissues with H&E indicated that the human liver tissue in chimeric mice responded differently than the mouse liver tissue to gamma radiation on the cellular level, as evidenced by differences in inflammation and cellular damage seen on histopathology. The gene expression data collected from the liver samples will also be presented, which potentially offers an explanation for the differential responses.

Honglu Wu↗

NASA NTRSDate not supplied

Comparison of Radiation-Induced Damage Between Livers From Control and Chimeric Mice

Honglu Wu↗