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

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At least 181 records · Page 10
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

SU-F-R-50: Radiation-Induced Changes in CT Number Histogram During Chemoradiation Therapy for Pancreatic Cancer

Purpose: In an effort of early assessment of treatment response, we investigate radiation induced changes in CT number histogram of GTV during the delivery of chemoradiation therapy (CRT) for pancreatic cancer. Methods: Diagnostic-quality CT data acquired daily during routine CT-guided CRT using a CT-on-rails for 20 pancreatic head cancer patients were analyzed. All patients were treated with a radiation dose of 50.4 in 28 fractions. On each daily CT set, the contours of the pancreatic head and the spinal cord were delineated. The Hounsfiled Units (HU) histogram in these contourswere extracted and processed using MATLAB. Eight parameters of the histogram including the mean HU over all the voxels, peak position, volume, standard deviation (SD), skewness, kurtosis, energy, and entropy were calculated for each fraction. The significances were inspected using paired two-tailed t-test and the correlations were analyzed using Spearman rank correlation tests. Results: In general, HU histogram in pancreatic head (but not in spinal cord) changed during the CRT delivery. Changes from the first to the last fraction in mean HU in pancreatic head ranged from −13.4 to 3.7 HU with an average of −4.4 HU, which was significant (P<0.001). Among other quantities, the volume decreased, the skewness increased (less skewed), and the kurtosis decreased (less sharp) during the CRT delivery. The changes of mean HU, volume, skewness, and kurtosis became significant after two weeks of treatment. Patient pathological response status is associated with the changes of SD (ΔSD), i.e., ΔSD= 1.85 (average of 7 patients) for good reponse, −0.08 (average of 6 patients) for moderate and poor response. Conclusion: Significant changes in HU histogram and the histogram-based metrics (e.g., meam HU, skewness, and kurtosis) in tumor were observed during the course of chemoradiation therapy for pancreas cancer. These changes may be potentially used for early assessment of treatment response.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-J-137: Intrafractional Change of the Relationship Between Internal Fiducials and External Breathing Signal in Pancreatic Cancer Stereotactic Body Radiation Therapy

Purpose: The use of respiratory gating for management of breathing motion during stereotactic body radiation therapy (SBRT) relies on a consistent relationship between the breathing signal and the actual position of the internal target. This relationship was investigated in patients treated for pancreatic cancer. Methods: Four patients with pancreatic cancer undergoing SBRT that had implanted fiducials in the tumor were included in this study. Treatment plans were generated based on the exhale phases (30–70%) from the pre-treatment 4DCT. The margin between the internal target volume (ITV) and the planning target volume was three mm. After patient setup using cone-beam CT, simultaneous fluoroscopic imaging and breathing motion monitoring were used during at least three breathing cycles to verify the fiducial position and to optimize the gating window. After treatment, fluoroscopic images were acquired for verification purposes and exported for retrospective analyses. Fiducial positions were determined using a template-matching algorithm. For each dataset, we established a linear relationship between the fiducial position and the anterior-posterior (AP) breathing signal. The relationships before and after treatment were compared and the dose distribution impact evaluated. Results: Seven pre- and post-treatment fluoroscopic pairs were available for fiducial position analyses in the superior-inferior (SI) and left-right (LR) directions, and five in the AP direction. Time between image acquisitions was typically six to eight minutes. An average absolute change of 1.2±0.7 mm (range: 0.1–1.7) of the SI fiducial position relative to the external signal was found. Corresponding numbers for the LR and AP fiducial positions were 0.9±1.0 mm (range: 0.2–3.0) and 0.5±0.4 mm (range: 0.2–1.2), respectively. The dose distribution impact was small in both the ITV and organs-at-risk. Conclusion: The relationship change between fiducial position and external breathing signal has been observed to be about 1 mm in four pancreas SBRT patients, leading to small dose distribution impact. Pettersson and Cervino are funded by a Varian Medical Systems grant.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-J-158: Respiratory Motion Resolved, Self-Gated 4D-MRI Using Rotating Cartesian K-Space Sampling

Purpose: Dynamic MRI has been used to quantify respiratory motion of abdominal organs in radiation treatment planning. Many existing 4D-MRI methods based on 2D acquisitions suffer from limited slice resolution and additional stitching artifacts when evaluated in 3D{sup 1}. To address these issues, we developed a 4D-MRI (3D dynamic) technique with true 3D k-space encoding and respiratory motion self-gating. Methods: The 3D k-space was acquired using a Rotating Cartesian K-space (ROCK) pattern, where the Cartesian grid was reordered in a quasi-spiral fashion with each spiral arm rotated using golden angle{sup 2}. Each quasi-spiral arm started with the k-space center-line, which were used as self-gating{sup 3} signal for respiratory motion estimation. The acquired k-space data was then binned into 8 respiratory phases and the golden angle ensures a near-uniform k-space sampling in each phase. Finally, dynamic 3D images were reconstructed using the ESPIRiT technique{sup 4}. 4D-MRI was performed on 6 healthy volunteers, using the following parameters (bSSFP, Fat-Sat, TE/TR=2ms/4ms, matrix size=500×350×120, resolution=1×1×1.2mm, TA=5min, 8 respiratory phases). Supplemental 2D real-time images were acquired in 9 different planes. Dynamic locations of the diaphragm dome and left kidney were measured from both 4D and 2D images. The same protocol was also performed on a MRI-compatible motion phantom where the motion was programmed with different amplitude (10–30mm) and frequency (3–10/min). Results: High resolution 4D-MRI were obtained successfully in 5 minutes. Quantitative motion measurements from 4D-MRI agree with the ones from 2D CINE (<5% error). The 4D images are free of the stitching artifacts and their near-isotropic resolution facilitates 3D visualization and segmentation of abdominal organs such as the liver, kidney and pancreas. Conclusion: Our preliminary studies demonstrated a novel ROCK 4D-MRI technique with true 3D k-space encoding and respiratory motion self-gating. The technique leads to high-resolution and artifacts-free 4D images for improved abdominal organ motion studies. K.S acknowledges funding support from NIH R01CA188300.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-T-90: Patterns of Electron IORT Treatments in the U.S., Europe and Asia

Purpose: We analyzed data collected from worldwide centers active in electron IORT with a focus on the technical variables of the treatment. Particular attention was given to the dominant tumor sites. Methods: 54 Mobetron users from 14 countries in clinical operation prior to December 31, 2014, were invited to participate in this study. 29 centers contributed to this survey in sufficient detail to be included in this report. 6,035 patients were treated since 1997. Parameters were analyzed separately for each treatment site. However, special attention was given to the breast cancer, which turned out to be dominant tumor site. Results: The average number of patients treated per year in each center was 41 and exceeded 100 patients/year in 3 centers. For data received, 70% of patients worldwide were treated for breast cancer (93% in Europe, 14% in the U.S. and 21% in Asia). In 31% of cases electron IORT was the only breast irradiation. In breast patients, 9 MeV was used in 50% cases; 4MeV, 6MeV and 12MeV in 2%, 25% and 23% of cases respectively. 85% of patients were treated with field sizes between 4 and 6 cm and 35% of them were treated with 1/2 cm sized applicators. Beveled applicators (0°, 15° and 30° tips) were used in 51%, 33% and 16% of cases respectively. In 55% cases bolus was required with 5mm bolus used twice as often as 10mm. Chest-wall protectors were used in 53% of treatment procedures. For Non-breast data, main sites were: colorectal tumors (31%), pancreatic cancers (20%), extremity sarcomas (13%) and retroperitoneal sarcomas (5%). Conclusion: A large variety of tumors have been treated with IORT, with breast, colorectal, pancreas and sarcomas being the most frequently treated sites. This survey shows the most common applicators and energies used to treat each tumor site.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-F-T-563: Delivered Dose Reconstruction of Moving Targets for Gated Volumetric Modulated Arc Therapy (VMAT)

Purpose: Actual delivered dose of moving tumors treated with gated volumetric arc therapy (VMAT) may significantly differ from the planned dose assuming static target. In this study, we developed a method which reconstructs actual delivered dose distribution of moving target by taking into account both tumor motion and dynamic beam delivery of gated VMAT, and applied to abdominal tumors. Methods: Fifteen dual-arc VMAT plans (Eclipse, Varian Medical Systems) for 5 lung, 5 pancreatic, and 5 liver cancer patients treated with gated VMAT stereotactic body radiotherapy (SBRT) were studied. For reconstruction of the delivered dose distribution, we divided each original arc beam into control-point-wise sub-beams, and applied beam isocenter shifting to each sub-beam to reflect the tumor motion. The tumor positions as a function of beam delivery were estimated by synchronizing the beam delivery with the respiratory signal which acquired during treatment. For this purpose, an in-house program (MATLAB, Mathworks) was developed to convert the original DICOM plan data into motion-involved treatment plan. The motion-involved DICOM plan was imported into Eclipse for dose calculation. The reconstructed delivered dose was compared to the plan dose using the dose coverage of gross tumor volume (GTV) and dose distribution of organs at risk (OAR). Results: The mean GTV dose coverage difference between the reconstructed delivered dose and the plan dose was 0.2 % in lung and pancreas cases, and no difference in liver cases. Mean D1000cc of ipsilateral lungs was reduced (0.8 ± 1.4cGy). Conclusion: We successfully developed a method of delivered dose reconstruction taking into account both respiratory tumor motion and dynamic beam delivery, and applied it to abdominal tumors treated with gated VAMT. No significant deterioration of delivered dose distribution indicates that interplay effect would be minimal even in the case of gated SBRT. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2015038710)

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

MO-DE-207A-02: A Feature-Preserving Image Reconstruction Method for Improved Pancreaticlesion Classification in Diagnostic CT Imaging

Purpose: To develop a feature-preserving model based image reconstruction (MBIR) method that improves performance in pancreatic lesion classification at equal or reduced radiation dose. Methods: A set of pancreatic lesion models was created with both benign and premalignant lesion types. These two classes of lesions are distinguished by their fine internal structures; their delineation is therefore crucial to the task of pancreatic lesion classification. To reduce image noise while preserving the features of the lesions, we developed a MBIR method with curvature-based regularization. The novel regularization encourages formation of smooth surfaces that model both the exterior shape and the internal features of pancreatic lesions. Given that the curvature depends on the unknown image, image reconstruction or denoising becomes a non-convex optimization problem; to address this issue an iterative-reweighting scheme was used to calculate and update the curvature using the image from the previous iteration. Evaluation was carried out with insertion of the lesion models into the pancreas of a patient CT image. Results: Visual inspection was used to compare conventional TV regularization with our curvature-based regularization. Several penalty-strengths were considered for TV regularization, all of which resulted in erasing portions of the septation (thin partition) in a premalignant lesion. At matched noise variance (50% noise reduction in the patient stomach region), the connectivity of the septation was well preserved using the proposed curvature-based method. Conclusion: The curvature-based regularization is able to reduce image noise while simultaneously preserving the lesion features. This method could potentially improve task performance for pancreatic lesion classification at equal or reduced radiation dose. The result is of high significance for longitudinal surveillance studies of patients with pancreatic cysts, which may develop into pancreatic cancer. The Senior Author receives financial support from Siemens GmbH Healthcare.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

MO-FG-BRA-09: Towards an Optimal Breath-Holding Procedure for Radiotherapy: Differences in Organ Motion During Inhalation and Exhalation Breath-Holds

Purpose: Breath-holding (BH) is often used to reduce organ motion during radiotherapy. The aim of this study was to determine the differences in pancreatic and diaphragmatic motion during BH between inhalation and exhalation BHs with variable lung volumes and to investigate whether motion increases/decreases during BH. Methods: Sixteen healthy volunteers were asked to perform four different 60-second BHs, from fully inflated to fully deflated lungs (i.e. lung volumes of: 100%, ∼70%, ∼30% and 0% of inspiratory capacity) three times (total of 192 BHs). During each BH, we obtained single-slice (coronal) magnetic-resonance scans with spatial resolution 0.93×0.93×8.0 mm3 and temporal resolution 0.6 s. We used 2-dimensional image correlation to obtain the motion of pancreatic head and diaphragm during BH. Motion magnitude in inferior-superior direction was obtained by determining the maximum displacement during BH. Results: Pancreatic and diaphragmatic drifts occurred during BH and were mostly in the superior direction. We observed significantly smaller pancreatic and diaphragmatic motion magnitudes in inferior-superior direction during exhalation BHs (BH{sub 30%} and BH{sub 0%}) compared to inhalation BHs (BH{sub 100%} and BH{sub 70%}). The mean motion magnitudes of the pancreatic head were 7.0, 6.5, 4.4 and 4.2 mm during BH{sub 100%}, BH{sub 70%}, BH{sub 30%} and BH{sub 0%}, respectively, and mean BH durations were 59.9, 59.1, 59.0 and 52.7 s. For the diaphragm, mean motion magnitudes were 9.8, 9.0, 5.6 and 4.3 mm, respectively. When considering 30-second BHs, as often used in the clinic, the motion was most pronounced during the first 10 s and excluding these from the analysis (yielding an effective BH period of 20 s) significantly reduced (P≤0.002) organ motion. Conclusion: Organ motion was significantly smaller during exhalation BHs compared to inhalation BHs. Also, motion was largest at the start of BH. Hence, waiting for 10 s may significantly decrease motion of the pancreas and diaphragm during treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-CD-207A-04: Optimized Respiratory Gating for Abnormal Breathers in Pancreatic SBRT

Purpose: Pancreatic SBRT is uniquely challenging due to both the erratic/unstable motion of the pancreas and the close proximity of the radiosensitive small bowel. Respiratory gating can mitigate this effect, but the irregularity of motion severely affects traditional phase-based gating. The purpose of this study was to analyze real-time motion data of pancreatic tumors to optimize the efficacy and accuracy of respiratory gating, with the overall goal of enabling dose escalated pancreatic SBRT. Methods: Fifteen pancreatic SBRT patients received 30–33 Gy in 5 fractions on a Varian TrueBeam STx unit. Abdominal compression was used to reduce the amplitude of tumor motion, and daily cone-beam computed tomography (CBCT) scans were acquired prior to each treatment for target localization purposes. For this study, breathing data (phase and amplitude) were collected during each CBCT scan using Varian’s Real-Time Position Management system. An in-house template matching technique was used to track the superior-inferior motion of implanted fiducial markers in CBCT projection images. Using tumor motion and breathing data, phase-based or amplitude-based respiratory gating was simulated for all 75 fractions, targeting either end-exhalation or end-inhalation phases of breathing. Results: For the average patient, gating at end-exhalation offered the best reductions in effective motion for equal duty cycles. However, optimal central phase angle varied widely (range: 0–92%, mean±SD: 49±12%), and phase-based gating windows typically associated with end-exhalation (i.e., “30–70%”) were rarely ideal. Amplitude-based gating significantly outperformed phase-based gating, with average effective ranges for amplitude-based gating 25% lower than phase-based gating ranges (as much as 73% lower). Amplitude-based gating was consistently better suited to accommodate abnormal breathing patterns. For both phase-based and amplitude-based gating, end-exhalation provided significantly better results than end-inhalation. Conclusion: Amplitude-based gating reliably outperformed phase-based gating, and end-exhalation was more suitable than end-inhalation. These results will be used to guide future dose-escalation trials. Research funding provided by Varian Medical Systems to Miften and Jones.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-EF-207A-02: Imaging Pancreatic Î{sup 2}-Cell Function with 51/52Mn-PET

Purpose: To image β-cells noninvasively using radio-manganese PET and to develop efficient small cyclotron production of {sup 51}Mn (t1/2=46m, β{sup +}=97%) and {sup 52}Mn (t1/2=5.6d, β{sup +}=29%). Methods: {sup 51}Mn and {sup 52}Mn were produced by 16 MeV proton irradiation (GE PETtrace) of electrodeposited {sup 54}Fe on silver and Cr metal pressed into a silver disc, respectively. {sup 51}Mn was radiochemically isolated from target material by anion exchange chromatography and {sup 52}Mn was isolated by ethanolic anion exchange trap-and-release. A final injectable product of {sup 51}Mn{sup 2+} or {sup 52}Mn{sup 2+} was obtained in 0.01M pH 6.0 NaOAc. To assess pancreatic uptake, fasted ICR mice were administered and intravenous bolus or infusion of {sup 52}Mn{sup 2+}. Additionally, to demonstrate the correlation between β-cell function and {sup 52}Mn{sup 2+} pancreatic uptake, prior to tracer administration groups of ICR mice were administered glibenclamide (5mg/kg) and diazoxide (20 mg/kg) as an insulin release stimulator and blocker, respectively. To validate PET ROI quantification, ex vivo biodistribtution studies were conducted on each subject after the final imaging time-point. Results: Dynamic PET data using a left atrium ROI revealed that {sup 52}Mn{sup 2+} cleared from the blood with a 10 second half-life. Significant uptake was seen in the pancreas (approximately 20% ID/g, SUVmean= 5.5), liver, kidneys, intestine, heart, and thyroid. Pancreatic uptake was found to be highly sensitive to volatile anesthesia administration (p=0.0002), insulin release stimulation by glibenclamide (p=0.017), and by insulin release inhibition by diazoxide (p=0.046). Excellent agreement was found between in vivo PET ROI quantification and ex vivo biodistribution measurements. Conclusion: This work demonstrates the feasibility of using radiomanganese-PET for measuring functional β-cell mass in vivo. The decay characteristics and dosimetric properties of {sup 51}Mn are well suited for clinical PET, which will allow for rapid translation and application.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Robotic Extended Right Hemicolectomy with Complete Mesocolic Excision and D3 Lymph Node Dissection

Background: Recent studies have shown the benefits of complete mesocolic excision and extended lymphadenectomy (D3 lymph node dissection) in patients with colon cancer.1{sup –}3 Methods: We present the case of a 62-year-old male with hepatic flexure adenocarcinoma. No metastatic disease was identified by computed tomography. A robot-assisted extended right hemicolectomy with complete mesocolic excision, D3 lymph node dissection, and resection of the mesentery with intact visceral peritoneum was performed. Results: The trocars are placed in the right lower (8 mm), lower midline (8 mm), and left upper (12 mm) quadrants. The camera port is placed superior to the umbilicus, and the assistant port is placed in the left lower quadrant. The robotic right lower port is used to place the cecum on tension in order to outline the ileocolic pedicle. The assistant retracts the transverse colon cephalad to outline the superior mesenteric artery and vein. Using two robotic arms, the surgeon begins dissection over the superior mesenteric vein inferior to the ileocolic pedicle. Cephalad dissection along the superior mesenteric vein proceeds with reflection of the mesentery and D3 lymph nodes laterally to allow en bloc resection. The ileocolic and middle colic vessels are identified, ligated and divided at their origins. The plane is then developed between the right colon mesentery and the retroperitoneum, including Gerota’s fascia, duodenum, and head of the pancreas, in a medial-to-lateral fashion, with care taken to ensure an intact visceral peritoneum is maintained. The proximal transverse colon, hepatic flexure, and ascending colon are mobilized by taking down lateral attachments. The intervening mesentery is transected, and perfusion is assessed with indocyanine green fluorescence imaging. An intracorporeal, isoperistaltic, side-to-side anastomosis is performed using the 45-mm robotic stapler. The common enterotomy is sewn closed in two layers. Pathology showed T3N0 adenocarcinoma with all negative margins. Conclusion: Extended right hemicolectomy with complete mesocolic excision and D3 lymph node dissection is facilitated by a robotic approach, which improves visualization and instrument dexterity.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Practical management in Wolcott‐Rallison syndrome with associated hypothyroidism, neutropenia, and recurrent liver failure: A case report

Key Clinical Message Wolcott‐Rallison syndrome is a rare genetic syndrome of neonatal diabetes, liver failure, and growth retardation. We present a case with a EIF2AK3 p.(Arg902Ter) mutation, additionally complicated by hypothyroidism, impaired renal function, and exocrine pancreas insufficiency, focusing on clinical management. For its optimization, thorough care of multiple organ systems is needed.

Lundgren, Markus↗
DOE OSTI2018

Weight change since age 20 and incident risk of obesity‐related cancer in Japan: a pooled analysis of the Miyagi Cohort Study and the Ohsaki Cohort Study

It is unclear whether weight change during adulthood affects the risk of obesity‐related cancers such as those of the esophagus, colorectum, pancreas, breast, endometrium, and kidney among Japanese, where obesity is less frequent and less severe. We examined the association between weight change during adulthood and the risk of obesity‐related cancer among Japanese by conducting a pooled analysis of two prospective studies of residents in Miyagi Prefecture, Japan. A total of 78,743 persons (40,422 women and 38,321 men) aged 40–79 years participated in the Miyagi Cohort Study in 1990 and in the Ohsaki Cohort Study in 1994. Weight change since age 20 was divided into four categories (weight loss; stable weight; moderate weight gain; high weight gain). Cox proportional hazards regression analysis was used to estimate the multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for obesity‐related cancer incidence. During 1,057,899 person‐years of follow up, 4,467 cases of obesity‐related cancer (women; 1,916 cases, men; 2,551cases) were identified. In women, compared to the stable weight, weight gain was associated with an increased risk of obesity‐related cancer (moderate weight gain; HRs = 1.10, 95%CIs: 0.97–1.26, high weight gain; HRs = 1.29, 95%CIs: 1.14–1.47). The results indicate that weight gain since age 20 was associated with a significantly increased risk of obesity‐related cancer among Japanese women. By contrast, in men, our study found that weight change is not associated with the incidence of obesity‐related cancer.

Wakamatsu, Mano↗
DOE OSTI2021

Long‐term drench of exopolysaccharide from Leuconostoc pseudomesenteroides XG5 protects against type 1 diabetes of NOD mice via stimulating GLP ‐1 secretion

Abstract BACKGROUND Type 1 diabetes is an autoimmune disease that results in the specific destruction of insulin‐producing beta cells in the pancreas. The aim of this study was to investigate the mechanism of exopolysaccharide from Leuconostoc pseudomesenteroides XG5 (XG5 EPS) against type 1 diabetes. RESULTS Long‐term drench of XG5 EPS delayed the onset of autoimmune diabetes and had fewer islets with high‐grade infiltration (an insulitis score of 3 or 4) than untreated NOD mice. Oral administration of 50 mg kg −1 d −1 XG5 EPS increased the insulin and glucagon‐like peptide‐1 (GLP‐1) levels of serum, stimulated GLP‐1 secretion and upregulated gcg mRNA expression of colon in NOD mice. Moreover, oral administration of 50 mg kg −1 d −1 XG5 EPS significantly increased total short‐chain fatty acids levels in the colon contents, especially those of acetic acid and butyric acid. In NCI‐H716 cells, 500 and 1000 μmol L −1 sodium butyrate promoted the secretion of GLP‐1 and upregulated the mRNA expression of gcg and PC3 , while XG5 EPS and sodium acetate did not stimulate the GLP‐1 secretion. Therefore, long‐term drench of XG5 EPS delayed the onset of autoimmune diabetes, which may be directly correlated with the increase of butyrate in the colon of NOD mice. CONCLUSION Long‐term drench of 50 mg kg −1 d −1 XG5 EPS promoted the expression and secretion of GLP‐1 by increasing the production of butyric acid, thereby delaying T1D onset in NOD mice. © 2021 Society of Chemical Industry.

Pan, Lei↗
DOE OSTI2024

Reduction of Chemokine CXCL9 Expression by Omega-3 Fatty Acids via ADP-Ribosylhydrolase ARH3 in MIN6 Insulin-Producing Cells

Type 1 diabetes (T1D) results from the autoimmune destruction of the insulin-producing β cells of the pancreas. Omega-3 fatty acids protect β cells and reduce the incidence of T1D, but the mechanism is poorly understood. We have shown that omega-3 fatty acids reduce pro-inflammatory cytokine-mediated β-cell apoptosis by upregulating the expression of the ADP-ribosylhydrolase ARH3. Here, we further investigate the β-cell protection mechanism of ARH3 by performing siRNA analysis of its gene Adprhl2 in MIN6 insulin-producing cells, subsequent treatment with a cocktail of the pro-inflammatory cytokines IL-1β + IFN-γ + TNF-α, followed by proteomics analysis. ARH3 regulated proteins from several pathways related to the nucleus (splicing, RNA surveillance, and nucleocytoplasmic transport), mitochondria (metabolic pathways), and endoplasmic reticulum (protein folding). ARH3 also regulated the levels of proteins related to antigen processing and presentation, and the chemokine-signaling pathway. We further studied the role of ARH3 in regulating the chemokine CXCL9. We found that ARH3 reduces the cytokine-induced expression of CXCL9, which is dependent on omega-3 fatty acids. In conclusion, we demonstrate that omega-3 fatty acids regulate CXCL9 expression via ARH3, which may have a role in protecting β cells from immune attack thereby preventing T1D development.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

High-throughput screening identifies small molecules that bind to the RAS:SOS:RAS complex and perturb RAS signaling

K-RAS is mutated in approximately 30% of human cancers, resulting in increased RAS signaling and tumor growth. Thus, RAS is a highly validated therapeutic target, especially in tumors of the pancreas, lung and colon. Although directly targeting RAS has proven to be challenging, it may be possible to target other proteins involved in RAS signaling, such as the guanine nucleotide exchange factor Son of Sevenless (SOS). We have previously reported on the discovery of small molecules that bind to SOS1, activate SOS-mediated nucleotide exchange on RAS, and paradoxically inhibit ERK phosphorylation. In this paper, we describe the discovery of additional, structurally diverse small molecules that also bind to SOS1 in the same pocket and elicit similar biological effects. We tested>160,000 compounds in a fluorescence-based assay to assess their effects on SOS-mediated nucleotide exchange. X-Ray structures revealed that these small molecules bind to the CDC25 domain of SOS1. Compounds that elicited high levels of nucleotide exchange activity in vitro increased RAS-GTP levels in cells, and inhibited phospho ERK levels at higher treatment concentrations. The identification of structurally diverse SOS1 binding ligands may assist in the discovery of new molecules designed to target RASdriven tumors.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2017

Nuclear import of Nkx2-2 is mediated by multiple pathways

Nkx2-2 homeoprotein is essential for the development of the central nervous system and pancreas. Although the nuclear localization signals of Nkx2-2 have been identified, the responsible transport receptor is still unknown. Here, we demonstrate that imp α1 not only interacts with Nkx2-2 but also transports it into the nucleus in vitro by acting together with imp β1. However, the nuclear import of Nkx2-2 in cells was not inhibited in response to knockdown expression of endogenous imp β1 or over-expression of Bimax2. Furthermore, imp β1 and imp 13, but not imp 4, directly interact with Nkx2-2 and are capable of transporting Nkx2-2 in an in vitro import assay. By GST pull-down assay, we demonstrate that mutation of NLS1 or NLS2 has no effect on interaction with imp α1 or imp 13, but significantly reduced binding to imp β1. Thus, the nuclear import of Nkx2-2 is mediated not only by the classical import pathway but also directly by imp β1 or imp 13.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

The Long Noncoding RNA Paupar Modulates PAX6 Regulatory Activities to Promote Alpha Cell Development and Function

Many studies have highlighted the role of dysregulated glucagon secretion in the etiology of hyperglycemia and diabetes. Accordingly, understanding the mechanisms underlying pancreatic islet ? cell development and function has important implications for the discovery of new therapies for diabetes. In this study, comparative transcriptome analyses between embryonic mouse pancreas and adult mouse islets identified several pancreatic lncRNAs that lie in close proximity to essential pancreatic transcription factors, including the Pax6-associated lncRNA Paupar. We demonstrate that Paupar is enriched in glucagon-producing ? cells where it promotes the alternative splicing of Pax6 to an isoform required for activation of essential ??cell genes. Consistently, deletion of Paupar in mice resulted in dysregulation of PAX6 ? cell target genes and corresponding ? cell dysfunction, including blunted glucagon secretion. These findings illustrate a distinct mechanism by which a pancreatic lncRNA can coordinate glucose homeostasis by cell-specific regulation of a broadly expressed transcription factor.

diabetes, pancreatic islets, glucagon, alpha cells↗
DOE OSTI2022

Proteomic Profiling of Intra-Islet Features Reveals Substructure-Specific Protein Signatures

Despite their diminutive size, islets of Langerhans play a large role in maintaining systemic energy balance in the body. New technologies have enabled us to go from studying the whole pancreas, to isolated whole islets, to partial islet sections, and now to islet substructures isolated from within the islet. Using a microfluidic nanodroplet-based proteomics platform coupled with laser capture microdissection (LCM), we present an in-depth investigation of protein profiles specific to regions within the islet. These regions studied include the vascular tissue containing interface boundary, micro-vascular tissue internal to the islet, isolated endocrine cells, islet sections with vasculature intact, and finally acinar tissue from around the islet. Unique protein signatures observed in the inner vasculature potentially indicate increased innervation and intra-islet neuron-like crosstalk compared to external vasculature. We also demonstrate the utility of these data for isolating localized structure-specific drug-target interactions using existing protein/drug binding databases.

59 BASIC BIOLOGICAL SCIENCES↗