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At least 487 records · Page 27
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Temporal regularization of ultrasound-based liver motion estimation for image-guided radiation therapy

Purpose: Ultrasound-based motion estimation is an expanding subfield of image-guided radiation therapy. Although ultrasound can detect tissue motion that is a fraction of a millimeter, its accuracy is variable. For controlling linear accelerator tracking and gating, ultrasound motion estimates must remain highly accurate throughout the imaging sequence. This study presents a temporal regularization method for correlation-based template matching which aims to improve the accuracy of motion estimates. Methods: Liver ultrasound sequences (15–23 Hz imaging rate, 2.5–5.5 min length) from ten healthy volunteers under free breathing were used. Anatomical features (blood vessels) in each sequence were manually annotated for comparison with normalized cross-correlation based template matching. Five sequences from a Siemens Acuson™ scanner were used for algorithm development (training set). Results from incremental tracking (IT) were compared with a temporal regularization method, which included a highly specific similarity metric and state observer, known as the α–β filter/similarity threshold (ABST). A further five sequences from an Elekta Clarity™ system were used for validation, without alteration of the tracking algorithm (validation set). Results: Overall, the ABST method produced marked improvements in vessel tracking accuracy. For the training set, the mean and 95th percentile (95%) errors (defined as the difference from manual annotations) were 1.6 and 1.4 mm, respectively (compared to 6.2 and 9.1 mm, respectively, for IT). For each sequence, the use of the state observer leads to improvement in the 95% error. For the validation set, the mean and 95% errors for the ABST method were 0.8 and 1.5 mm, respectively. Conclusions: Ultrasound-based motion estimation has potential to monitor liver translation over long time periods with high accuracy. Nonrigid motion (strain) and the quality of the ultrasound data are likely to have an impact on tracking performance. A future study will investigate spatial uniformity of motion and its effect on the motion estimation errors.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2016

SU-D-BRB-01: A Comparison of Learning Methods for Knowledge Based Dose Prediction for Coplanar and Non-Coplanar Liver Radiotherapy

Purpose: The predictive power of knowledge based planning (KBP) has considerable potential in the development of automated treatment planning. Here, we examine the predictive capabilities and accuracy of previously reported KBP methods, as well as an artificial neural networks (ANN) method. Furthermore, we compare the predictive accuracy of these methods on coplanar volumetric-modulated arc therapy (VMAT) and non-coplanar 4π radiotherapy. Methods: 30 liver SBRT patients previously treated using coplanar VMAT were selected for this study. The patients were re-planned using 4π radiotherapy, which involves 20 optimally selected non-coplanar IMRT fields. ANNs were used to incorporate enhanced geometric information including liver and PTV size, prescription dose, patient girth, and proximity to beams. The performance of ANN was compared to three methods from statistical voxel dose learning (SVDL), wherein the doses of voxels sharing the same distance to the PTV are approximated by either taking the median of the distribution, non-parametric fitting, or skew-normal fitting. These three methods were shown to be capable of predicting DVH, but only median approximation can predict 3D dose. Prediction methods were tested using leave-one-out cross-validation tests and evaluated using residual sum of squares (RSS) for DVH and 3D dose predictions. Results: DVH prediction using non-parametric fitting had the lowest average RSS with 0.1176(4π) and 0.1633(VMAT), compared to 0.4879(4π) and 1.8744(VMAT) RSS for ANN. 3D dose prediction with median approximation had lower RSS with 12.02(4π) and 29.22(VMAT), compared to 27.95(4π) and 130.9(VMAT) for ANN. Conclusion: Paradoxically, although the ANNs included geometric features in addition to the distances to the PTV, it did not perform better in predicting DVH or 3D dose compared to simpler, faster methods based on the distances alone. The study further confirms that the prediction of 4π non-coplanar plans were more accurate than VMAT. NIH R43CA183390 and R01CA188300.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-J-136: Impact of Audiovisual Biofeedback On Interfraction Motion Over a Course of Liver Cancer Stereotactic Body Radiotherapy

Purpose: In abdominal radiotherapy inconsistent interfraction respiratory motion can result in deviations during treatment from what was planned in terms of target position and motion. Audiovisual biofeedback (AVB) is an interactive respiratory guide that produces a guiding interface that the patient follows over a course of radiotherapy to facilitate regular respiratory motion. This study assessed the impact of AVB on interfraction motion consistency over a course of liver cancer SBRT. Methods: Five liver cancer patients have been recruited into this study, 3 followed AVB over their course of SBRT and 2 were free breathing (FB). Respiratory signals from the Varian RPM were obtained during 4DCT and each treatment fraction. Respiratory signals were organized into 10 respiratory bins, and interfraction consistency was quantified by the difference between each treatment fraction respiratory bin and each respiratory bin from 4DCT. Interfraction consistency was considered as both the relative difference (as a percentage) and absolute difference (in centimeters) between treatment respiratory bins and 4DCT respiratory bins. Results: The relative difference between 4DCT and treatment respiratory bins was 22 ± 16% for FB, and 15 ± 10% for AVB, an improvement of 32% (p < 0.001) with AVB. The absolute difference between 4DCT and treatment respiratory bins was 0.15 ± 0.10 cm for FB, and 0.14 ± 0.13 cm for AVB, an improvement of 4% (p = 0.6) with AVB. Conclusion: This was the first study to compare the impact of AVB breathing guidance on interfraction motion consistency over a course of radiotherapy. AVB demonstrated to significantly reduce the relative difference between 4DCT and treatment respiratory motion, but the absolute differences were comparable, largely due to one AVB patient exhibiting a larger amplitude than the other patients. This study demonstrates the potential benefit of AVB in reducing motion variations during treatment from what was planned. Paul Keall, Sean Pollock, Ricky OBrien and Kuldeep Makhija are shareholders of Respiratory Innovations, an Australian company that is developing a device to improve breathing stability. No funding or support was provided by Respiratory Innovations. Paul Keall is one of the inventors of US patent # 7955270.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-J-224: Impact of 4D PET/CT On PERCIST Classification of Lung and Liver Metastases in NSLC and Colorectal Cancer

Purpose: To quantify the impact of 4D PET/CT on PERCIST metrics in lung and liver tumors in NSCLC and colorectal cancer patients. Methods: 32 patients presenting lung or liver tumors of 1–3 cm size affected by respiratory motion were scanned on a GE Discovery 690 PET/CT. The bed position with lesion(s) affected by motion was acquired in a 12 minute PET LIST mode and unlisted into 8 bins with respiratory gating. Three different CT maps were used for attenuation correction: a clinical helical CT (CT-clin), an average CT (CT-ave), and an 8-phase 4D CINE CT (CT-cine). All reconstructions were 3D OSEM, 2 iterations, 24 subsets, 6.4 Gaussian filtration, 192×192 matrix, non-TOF, and non-PSF. Reconstructions using CT-clin and CT-ave used only 3 out of the 12 minutes of the data (clinical protocol); all 12 minutes were used for the CT-cine reconstruction. The percent change of SUVbw-peak and SUVbw-max was calculated between PET-CTclin and PET-CTave. The same percent change was also calculated between PET-CTclin and PET-CTcine in each of the 8 bins and in the average of all bins. A 30% difference from PET-CTclin classified lesions as progressive metabolic disease (PMD) using maximum bin value and the average of eight bin values. Results: 30 lesions in 25 patients were evaluated. Using the bin with maximum SUVbw-peak and SUVbw-max difference, 4 and 13 lesions were classified as PMD, respectively. Using the average bin values for SUVbw-peak and SUVbw-max, 3 and 6 lesions were classified as PMD, respectively. Using PET-CTave values for SUVbw-peak and SUVbw-max, 4 and 3 lesions were classified as PMD, respectively. Conclusion: These results suggest that response evaluation in 4D PET/CT is dependent on SUV measurement (SUVpeak vs. SUVmax), number of bins (single or average), and the CT map used for attenuation correction.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-G-IeP4-10: Microimaging for Different Degrees of Human Cavernous Hemangioma of Liver by Using In-Line Phase-Contrast Imaging CT

Purpose: Cavernous hemangioma of the liver (CHL) is the most common benign solid tumor of the liver. In this study, we quantitative assessment the different degrees of CHL from microscopic viewpoint by using in-line phase-contrast imaging CT (ILPCI-CT). Methods: The experiments were performed at x-ray imaging and biomedical application beamline (BL13W1) of Shanghai Synchrotron Radiation Facility (SSRF) in China. Three typical specimens at different stages, i.e., mild, moderate and severe human CHL were imaged using ILPCI-CT at 16keV without contrast agents. The 3D visualization of different degrees of CHL samples were presented using ILPCI-CT. Additionally, quantitative evaluation of the CHL features, such as the range of hepatic sinusoid equivalent diameters in different degrees of CHL samples, the ratio of the hepatic sinusoid to the CHL tissue, were measured. Results: The planar image clearly displayed the dilated hepatic sinusoids in microns. There was no normal hepatic vascular found in the all CHL samples. Different stages of CHL samples were presented with vivid shapes and stereoscopic effects by using 3D visualization. The equivalent diameters of hepatic sinusoids in three degrees CHL were different. The equivalent diameters of the hepatic sinusoids in mild CHL, range from 60 to 120 µm. The equivalent diameters of the hepatic sinusoids in moderate CHL, range from 65 to 190 µm. The equivalent diameters of the hepatic sinusoids in severe CHL, range from 95 to 215 µm. The ratio of the hepatic sinusoid to the mild, moderate and severe CHL tissue were 3%, 16% and 21%, respectively. Conclusion: The results show that the high degree of sensitivity of the ILPCI-CT technique and demonstrate the feasibility of accurate visualization of different stage human CHL. ILPCI-CT may offers a potential use in non-invasive study and analysis of CHL.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

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

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

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Poster - 49: Assessment of Synchrony respiratory compensation error for CyberKnife liver treatment

The goal of this work is to quantify respiratory motion compensation errors for liver tumor patients treated by the CyberKnife system with Synchrony tracking, to identify patients with the smallest tracking errors and to eventually help coach patient’s breathing patterns to minimize dose delivery errors. The accuracy of CyberKnife Synchrony respiratory motion compensation was assessed for 37 patients treated for liver lesions by analyzing data from system logfiles. A predictive model is used to modulate the direction of individual beams during dose delivery based on the positions of internally implanted fiducials determined using an orthogonal x-ray imaging system and the current location of LED external markers. For each x-ray pair acquired, system logfiles report the prediction error, the difference between the measured and predicted fiducial positions, and the delivery error, which is an estimate of the statistical error in the model overcoming the latency between x-ray acquisition and robotic repositioning. The total error was calculated at the time of each x-ray pair, for the number of treatment fractions and the number of patients, giving the average respiratory motion compensation error in three dimensions. The 99{sup th} percentile for the total radial error is 3.85 mm, with the highest contribution of 2.79 mm in superior/inferior (S/I) direction. The absolute mean compensation error is 1.78 mm radially with a 1.27 mm contribution in the S/I direction. Regions of high total error may provide insight into features predicting groups of patients with larger or smaller total errors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Intrahepatic Recurrence Patterns Predict Survival After Resection of Colorectal Liver Metastases

Background: After resection of colorectal liver metastases (CLM), up to 40% of patients will develop intrahepatic recurrence. This study aims to identify patterns of intrahepatic recurrence and their impact on survival after preoperative chemotherapy and CLM resection. Methods: A retrospective review was performed of patients developing intrahepatic recurrence after CLM resection following preoperative chemotherapy. Prechemotherapy, preoperative, and postoperative computed tomography scans were reviewed. Recurrences were classified as in situ, de novo, or both in situ and de novo. Median follow-up was 42 months (range 2–144 months). Results: Among 223 patients meeting study criteria, intrahepatic recurrence was identified a median of 9 months after hepatectomy. Isolated de novo or in situ recurrence developed in 105 (47%) and 86 (39%) patients, respectively. Thirty-two patients (14%) developed both in situ and de novo recurrence, which was associated with significantly lower median overall survival of 33 months compared with 49 and 45 months with isolated in situ or de novo recurrence, respectively (p = 0.048). Among 118 patients (53%) who developed in situ recurrence as a component of disease relapse, recurrences resulted from disappearing or missed liver metastases in 47 patients (40%). Conclusions: An intrahepatic recurrence pattern of both in situ and de novo metastases after CLM resection following preoperative chemotherapy predicts significantly worse overall survival compared with isolated in situ or de novo recurrence.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Polycystic Liver Disease

A 77-year-old African American male presented with intermittent abdominal pain for one week. He denied nausea, vomiting, diarrhea, constipation, fevers, anorexia, or weight loss. He denied a family history of liver disease, recent travel, or history of intravenous drug abuse. His vital signs were normal. Labs revealed total bilirubin of 1.5 mg/dl, hypoalbuminaemia 3.0 gm/dl and prolonged prothrombin time of 14.8 sec. Computed Tomography of the abdomen and pelvis with contrast showed multiple hepatic cysts with the largest cyst occupying the right abdomen, measuring 20.6 cm (Panel A and). This cyst had predominantly fluid attenuation, but also contained several septations. The patient underwent laparoscopic fenestration of the large hepatic cyst with hepatic cyst wall biopsy. Pathology revealed blood without malignant cells. The patient tolerated the procedure well with improvement of his abdominal pain and normalization of his liver function tests and coagulation profile.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Dietary Sodium Butyrate Supplementation Attenuates the Detrimental Effects of High-Fat Diets on Growth Performance, Liver Health, and Disease Resistance in Grass Carp

Abstract An 8-week experiment was conducted to investigate the effects of sodium butyrate (NaBT) inclusion in high-fat (HF) diets on growth performance, liver health, and disease resistance in Grass Carp Ctenopharyngodon idella. Three diets (Control diet containing crude lipid at 58 g/kg, HF diet with 108-g/kg crude lipid, and NaBT diet with 108-g/kg crude lipid and 1-g/kg NaBT) were randomly assigned to nine tanks with 30 fish (9.50 ± 0.06 g) in each tank. After the feeding trial, disease resistance was assessed by injecting the fish with Aeromonas hydrophila. Compared to the Control diet group, the HF diet group showed lower specific growth rate, feed efficiency, and survival rate (15.7%) after the A. hydrophila challenge; significantly higher activity levels of alanine aminotransferase and aspartate aminotransferase in plasma; higher malondialdehyde content; higher messenger RNA (mRNA) expression of interleukin-8, cysteinyl aspartate specific protease (caspase) 9, and caspase 3; lower activity level of glutathione peroxidase; and lower mRNA expression of nuclear factor erythroid 2-related factor 2 in liver. However, the NaBT diet significantly increased fish growth performance and survival rate (39.7%) after the A. hydrophila challenge and reduced hepatic oxidative stress, inflammation, and apoptosis compared to the HF diet. In conclusion, NaBT can ameliorate the detrimental effects of HF diets on fish growth performance and fish health.

Gao, Shiyang↗
DOE OSTI2018

Mersalyl prevents the Tl+-induced permeability transition pore opening in the inner membrane of Ca2+-loaded rat liver mitochondria

Highlights: • Interdependent participation of ANT and PiC is proposed in Tl{sup +}-induced pore opening. • Hydrophilic reagent mersalyl (MSL) till 5 μM inhibited opening the Tl{sup +}-induced pore. • The inhibiting effect of MSL was enhanced in experiments with N-ethylmaleimide. • The MSL inhibition of the pore opening was maximal in the presence of ADP and CsA. • Ability of ADP to inhibit the pore decreased in experiments with 20 μM MSL. It was earlier shown that the calcium load of rat liver mitochondria in medium containing TlNO{sub 3} and KNO{sub 3} resulted in the Tl{sup +}-induced mitochondrial permeability transition pore (MPTP) opening in the inner membrane. This opening was accompanied by an increase in swelling and membrane potential dissipation and a decrease in state 3, state 4, and 2,4-dinitrophenol-uncoupled respiration. This respiratory decrease was markedly leveled by mersalyl (MSL), the phosphate symporter (PiC) inhibitor which poorly stimulated the calcium-induced swelling, but further increased the potential dissipation. All of these effects of Ca{sup 2+} and MSL were visibly reduced in the presence of the MPTP inhibitors (ADP, N-ethylmaleimide, and cyclosporine A). High MSL concentrations attenuated the ability of ADP to inhibit the MPTP. Our data suggest that the PiC can participate in the Tl{sup +}-induced MPTP opening in the inner membrane of Ca{sup 2+}-loaded rat liver mitochondria.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Inhibition of liver mitochondrial membrane permeability transition pore opening by quercetin and vitamin E in streptozotocin-induced diabetic rats

Highlights: • Quercetin and vitamin E after streptozotocin induction prevent hepatic tissues from oxidative stress. • Administration of quercetin and vitamin E significantly reduced the elevated levels of glucose, tissue peroxidation, and enzyme activity. • Quercetin and vitamin E reversed the opening of membrane permeability transition pore caused by induction of diabetes. • The result suggests that quercetin was more effective than vitamin E. Diabetes mellitus is a chronic metabolic disorder characterized by rise in blood glucose levels and generation of free radicals which could induce mitochondrial membrane permeability transition (MMPT) pore opening. This study examined the in vivo action of quercetin and vitamin E on MMPT in the liver of streptozotocin-induced diabetic rats orally pre-treated with 30 mg quercetin/kg body weight (STZQ), 10 mg vitamin E/kg body weight (STZVit.E) and 0.6 mg glibenclamide/kg body weight (STZG). Male albino wistar rats were used in the study and were injected intraperitonially with streptozotocin (STZ) (45 mg/kg body weight) in citrate buffer. The degrees of serum and tissue peroxidation, alanine and aspartate aminotransferase activity were investigated. MMPT pore was assessed as mitochondrial swelling and was monitored spectrophotometrically as changes in absorbance at 540 nm under succinate-energized condition. There was significant increase in serum glucose level, degree of tissue peroxidation, alanine and aspartate aminotransferase activity, cholesterol and triglycerides values in the diabetic control rats following streptozotocin induction. All the treatment had effect on the damage caused by streptozotocin. Quercetin exhibited the highest chemopreventive activity. Quercetin and vitamin E significantly reduced the blood glucose level, degree of tissue peroxidation and alanine and aspartate amino transferase activity. In vivo rat liver MMPT pore was opened in diabetic control rats and significantly inhibited in STZQ, STZV and STZG treated groups by 72.3%, 58.5% and 87.5% respectively. The activity of quercetin and vitamin E were substantiated by histopathological evaluation. Our study suggests that quercetin is an effective therapeutic agent for preventing hepatic tissues from oxidative stress resulting from streptozotocin-induced diabetes by inhibiting apoptotic processes in their target cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Anti-liver cancer activity in vitro and in vivo induced by 2-pyridyl 2,3-thiazole derivatives

A total of 24 hybrid compounds containing pyridyl and 1,3-thiazole moieties were screened against HL-60 (leukemia), MCF-7 (breast adenocarcinoma), HepG2 (hepatocellular carcinoma), NCI-H292 (lung carcinoma) human tumor cell lines and non-tumor cells (PBMC, human peripheral blood mononuclear cells). Most of them were highly potent in at least one cell line tested (IC{sub 50} ≤ 3 μM), being HL-60 the most sensitive and HepG2 the most resistant cell line. Among them, TAP-07 and TP-07 presented cytotoxic activity in all tumor cell lines, including HepG2 (IC{sub 50} 2.2 and 5.6 μM, respectively) without antiproliferative effects to normal cells (PBMC) (IC{sub 50} > 30 μM), making TAP-07 and TP-07, the compounds with the most favorable selectivity index. TAP-07 and TP-07 induced apoptosis in HepG2 cells and presented in vivo antitumor activity in hepatocellular xenograft cancer model in C.B-17 severe combined immunodeficient mice. Systemic toxicological verified by biochemical and histopathological techniques reveled no major signs of toxicity after treatment with TAP-07 and TP-07. Together the results indicated the anti-liver cancer activity of 2-pyridyl 2,3-thiazole derivatives. - Highlights: • 2-Pyridyl 2,3-thiazole derivatives induce selective cytotoxicity to cancer cell lines. • 2-Pyridyl 2,3-thiazole derivatives cause cell death by apoptosis in HepG2 cells. • 2-Pyridyl 2,3-thiazole derivatives inhibit the progression of xenograft HepG2 liver cancer in SCID mice. • 2-Pyridyl 2,3-thiazole derivatives present no major signs of toxicity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors

Pyruvate dehydrogenase kinases 1–4 (PDK1–4) negatively control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure, and cancer. We reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] (1) and PS10 [2-((2,4-dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] (2) that targeted the ATP-binding pocket in PDKs. Here, we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in 1 and 2 to the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor (S)-3-amino-4-(4-((2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)amino)piperidin-1-yl)-4-oxobutanamide (17) shows a ~8-fold lower IC 50 (58 nM) than 2 (456 nM). In the crystal structure, the asparagine moiety in 17 provides additional interactions with Glu-262 from PDK2. Treatment of diet-induced obese mice with 17 resulted in significant liver-specific augmentation of PDC activity, accompanied by improved glucose tolerance and drastically reduced hepatic steatosis. Furthermore, these findings support 17 as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity

Cullin-RING E3 ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2–3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Identification of potent and selective N -myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts

Drugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhibitors have failed due to their low selectivity over human NMTs. Herein, we apply a structure-guided hybridization approach combining chemical moieties of previously reported NMT inhibitors to develop the next generation of PvNMT inhibitors. A high-resolution crystal structure of PvNMT bound to a representative selective hybrid compound reveals a unique binding site architecture that includes a selective conformation of a key tyrosine residue. The hybridized compounds significantly decrease P. falciparum blood-stage parasite load and consistently exhibit dose-dependent inhibition of P. vivax liver stage schizonts and hypnozoites. Our data demonstrate that hybridized NMT inhibitors can be multistage antimalarials, targeting dormant and developing forms of liver and blood stage.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Measuring chronic liver disease mortality using an expanded cause of death definition and medical records in C onnecticut, 2004

Aim Chronic liver disease ( CLD ) is a leading cause of death and is defined based on a specific set of underlying cause‐of‐death codes on death certificates. This conventional approach to measuring CLD mortality underestimates the true mortality burden because it does not consider certain CLD conditions like viral hepatitis and hepatocellular carcinoma. We measured how much the conventional CLD mortality case definition will underestimate CLD mortality and described the distribution of CLD etiologies in C onnecticut. Methods We used 2004 Connecticut death certificates to estimate CLD mortality two ways. One way used the conventional definition and the other used an expanded definition that included more conditions suggestive of CLD . We compared the number of deaths identified using this expanded definition with the number identified using the conventional definition. Medical records were reviewed to confirm CLD deaths. Results Connecticut had 29 314 registered deaths in 2004. Of these, 282 (1.0%) were CLD deaths identified by the conventional CLD definition while 616 (2.1%) were CLD deaths defined by the expanded definition. Medical record review confirmed that most deaths identified by the expanded definition were CLD ‐related (550/616); this suggested a 15.8 deaths/100 000 population mortality rate. Among deaths for which hepatitis B , hepatitis C and alcoholic liver disease were identified during medical record review, only 8.6%, 45.4% and 36.5%, respectively, had that specific cause‐of‐death code cited on the death certificate. Conclusion An expanded CLD mortality case definition that incorporates multiple causes of death and additional CLD ‐related conditions will better estimate CLD mortality.

Ly, Kathleen N.↗
DOE OSTI2016

Hepatitis C virus dynamics and cellular gene expression in uPA-SCID chimeric mice with humanized livers during intravenous silibinin monotherapy

Legalon SIL (SIL) is a chemically hydrophilized version of silibinin, an extract of milk thistle ( Silybum marianum ) seeds that has exhibited hepatoprotective and antiviral effectiveness against hepatitis C virus (HCV) in patients leading to viral clearance in combination with ribavirin. In this paper, to elucidate the incompletely understood mode of action of SIL against HCV, mathematical modelling of HCV kinetics and human hepatocyte gene expression studies were performed in uPA-SCID-chimeric mice with humanized livers. Chronically HCV-infected mice (n = 15) were treated for 14 days with daily intravenous SIL at 469, 265 or 61.5 mg/kg. Serum HCV and human albumin (hAlb) were measured frequently, and liver HCV RNA was analysed at days 3 and 14. Microarray analysis of human hepatocyte gene expression was performed at days 0, 3 and 14 of treatment. While hAlb remained constant, a biphasic viral decline in serum was observed consisting of a rapid 1st phase followed by a second slower phase (or plateau with the two lower SIL dosings). SIL effectiveness in blocking viral production was similar among dosing groups (median ε = 77%). However, the rate of HCV-infected hepatocyte decline, δ, was dose-dependent. Intracellular HCV RNA levels correlated (r = 0.66, P = 0.01) with serum HCV RNA. Pathway analysis revealed increased anti-inflammatory and antiproliferative gene expression in human hepatocytes in SIL-treated mice. Finally, the results suggest that SIL could lead to a continuous second-phase viral decline, that is potentially viral clearance, in the absence of adaptive immune response along with increased anti-inflammatory and antiproliferative gene expression in human hepatocytes.

59 BASIC BIOLOGICAL SCIENCES↗