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All sourcesNASA NTRSDOE OSTI
NASA NTRS2012

Paramyxovirus Infection Mimics In Vivo Cellular Dynamics in Three-Demensional Human Bronchio-Epithelial Tissue-Like Assemblies

Respiratory syncytial virus and parainfluenza virus cause severe respiratory disease, especially in infants, children and the elderly. An in vitro model that accurately mimics infection of the human respiratory epithelium (HRE) would facilitate vaccine development greatly. Monolayer cultures traditionally used to study these viruses do not accurately and precisely differentiate the replication efficiencies of wild type and attenuated viruses. Therefore, we engineered novel three-dimensional (3D) tissue-like assemblies (TLAs) of human broncho-epithelial (HBE) cells to produce a more physiologically relevant in vitro model of the HRE. TLAs resemble HRE structurally and by expression of differentiated epithelial cell markers. Most significantly, wild type viruses exhibited a clear growth advantage over attenuated strains in TLAs unlike monolayer cultures. In addition, the TLAs responded to virus infection by secreting pro-inflammatory mediators similar to the respiratory epithelia of infected children. These characteristics make the TLA model a valuable platform technology to develop and evaluate live, attenuated respiratory virus vaccine candidates for human use. Respiratory virus diseases, the most frequent and least preventable of all infectious diseases, range in severity from the common cold to severe bronchiolitis and pneumonia . Two paramyxoviruses, respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3), are responsible for a majority of the most severe respiratory diseases of infants and young children. RSV causes 70% of all bronchiolitis cases and is a major cause of morbidity and mortality worldwide, especially in infants. PIV3 causes 10-15% of bronchiolitis and pneumonia during infancy, second only to RSV, and 40% of croup in infants To date, licensed vaccines are not available to prevent these respiratory diseases. At present, traditional monkey kidney (Vero and LLC-MK2) and human (HEp-2) tissue culture cells and small animal models (mouse, cotton rat, guinea pig, ferret, and hamster) fail to accurately imitate viral replication and human disease states (8). Lacking an authentic model has impeded the development and evaluation of live, attenuated vaccine candidates. Development of a physiologically relevant in vitro tissue culture model that reproduces characteristics of the HRE, the primary target of RSV and PIV3, would aid in predicting clinical attenuation and safety of vaccine candidates. Successful tissue engineering of a 3D human intestinal model using novel NASA technology inspired the development of a tri-culture 3D model for the HRE. Sequential layering of primary mesenchymal cells (comprised of normal human fibroblasts and endothelial cells) followed by BEAS-2B epithelial cells derived from human bronchi and tracheae were recapitulated on Cultisphere and/or cytodex3 microcarriers in cylindrical vessels that rotate horizontally creating an organized epithelial structure. Horizontal rotation randomizes the gravity vector modeling aspects of microgravity. Mesenchymal and epithelial cells grown under these conditions reproduce the structural organization, multi-cellular complexity, and differentiation state of the HRE. The opportunity to study respiratory viruses in a nasal epithelium model is invaluable because the most promising respiratory virus vaccine candidates are live attenuated viruses for intranasal administration. Here we characterize the interactions of respiratory viruses and epithelial cells grown under modeled microgravity in comparison to gravity-ladened monolayers. 3D HBE TLAs and traditional monolayers (2D) are infected at 35 C, the upper temperature of the upper HRE, to simulate in vivo infection conditions. Growth kinetics of wild type (wt) RSV and PIV3 viruses were compared in 2D and 3D cells to that of strains attenuated in humans or rhesus macaques. This novel 3D HBE model also offers an opportunity to study whether the epithelial cell function, especially in host defenses recapitulated by mimicking the structural organization of the HRE. In vivo, airway epithelial cells play a significant and dynamic role in host defense by blocking paracellular permeability and modulating airway function through cellular interactions or tight junctions. As regulators of the innate immune response, epithelial cells constitutively express cytokines, chemokines, and colony stimulating factors including RANTES, IL-8, IL-6, GM-CSF, and G-CSF for proactive host defense. In response to viral infection, epithelial cells induce potent immuno-modulatory and pro-inflammatory cytokines that recruit phagocytic and inflammatory cells to clear the virus and enhance protection. Although disease pathogenesis is classically attributed to the cytopathic effects of the pathogen, severe disease states associated with RSV and PIV3 are attributed to the inflammatory response, especially in infants. RSV is a potent inducer of cytokines and pro-inflammatory mediators in epithelial cells in vivo. A differentiated human epithelial model independent of the complete functional immune system will help elucidate the role of epithelial cells in respiratory disease. We reported here, virus and host cell interactions in 3D HBE TLAs are similar to that in vivo. Because the epithelial cell organization of the TLAs impacts not only the expression of airway epithelial characteristics, but also cellular communication, the TLAs represent a more physiologically relevant model of the HRE than BEAS-2B or other non-tumour monolayer models of respiratory disease. As a result, wild type respiratory viruses have a clear growth advantage over attenuated viruses in TLAs unlike traditional monolayers. In addition, the TLAs respond to wild type virus infection by secreting pro-inflammatory mediators characteristic of infected HRE. TLAs expressing microbial defense mechanisms provide an excellent model to study the interactions of respiratory pathogens with their host and to identify the innate immunity mediators. Therefore, 3D HBE TLAs offer advantages for the study of respiratory viruses and the development of viral vaccine candidates.

Deatly, Anne M.↗
DOE OSTI2025

Animal movement estimation and network-based epidemic modeling: Illustration for the swine industry in Iowa (US)

Animal movement plays a critical role in disease transmission between farms. However, in the United States, the lack of available animal shipment data, sometimes coupled with a lack of detailed information about farm demographics and characteristics, presents great challenges for epidemic modeling and prediction. In this study, we proposed a new method based on the maximum entropy to generate “synthetic” animal movement networks, considering available statistics about the premises operation type, operation size, and the distance between premises. We illustrated our method for the swine movement networks in Iowa and performed network analyses to gain insights into the swine industry. We then applied the generated networks to a network-based epidemic model to identify potential system vulnerabilities in terms of disease transmission. The model was parameterized for African Swine Fever (ASF) as the US swine industry is quite concerned about this disease. Results show that premises with a central role in the network are more vulnerable to disease outbreaks and play an important role in disease spread. Simulations with outbreaks starting from random farms reveal no significant large outbreaks, indicating the system’s relative robustness against arbitrary disease introductions. However, outbreaks originating from high out-degree farms can lead to large epidemic sizes. This underscores the importance for stakeholders and policymakers to continue improving animal movement records and traceability programs in the US and the value of making that data available to epidemiologists and modelers to better understand risk and inform strategies aimed to cost-effectively prevent and control disease transmission. Our approach could be easily adapted to estimate movement networks in other animal production systems and to inform disease spread models for various infectious diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Reduction of ethanol yield from switchgrass infected with rust caused by Puccinia emaculata

Switchgrass ( Panicum virgatum ) is an important biofuel crop candidate thought to have low disease susceptibility. As switchgrass production becomes more prevalent, monoculture and production fields in close proximity to one another may increase the spread and severity of diseases such as switchgrass rust caused by the pathogen Puccinia emaculata . The objective of this research was to examine the impact of rust on ethanol yield in switchgrass. In 2010 and 2012, naturally infected leaves from field-grown Alamo and Kanlow in Knoxville, TN (2010, 2012) and Crossville, TN (2012) were visually categorized as exhibiting low, medium, or high disease based on the degree of chlorosis and sporulation. P. emaculata was isolated from each disease range to confirm infection. Samples from 2010 were acid/heat pretreated and subjected to two runs of simultaneous saccharification and fermentation (SSF) with Saccharomyces cerevisiae D 5 A to measure ethanol yield. Near-infrared spectroscopy (NIRS) was used to estimate ethanol yield for 2012 samples. SSF and NIRS data were analyzed separately using ANOVA. Disease level effects were significant within both models (P < 0.05) and both models explained a large amount of variation in ETOH (SSF: R 2 = 0.99, NIRS: R 2 = 0.99). In the SSF dataset, ethanol was reduced by 35 % in samples exhibiting medium disease symptoms and by 55 % in samples exhibiting high disease symptoms. In the NIRS dataset, estimated ethanol was reduced by 10 % in samples exhibiting medium disease symptoms and by 21 % in samples exhibiting high disease symptoms. Lastly, results indicate that switchgrass rust will likely have a negative impact on ethanol yield in switchgrass grown as a biofuel crop.

09 BIOMASS FUELS↗
DOE OSTI2015

Definition and Validation of “Favorable High-Risk Prostate Cancer”: Implications for Personalizing Treatment of Radiation-Managed Patients

Purpose: To define and validate a classification of favorable high-risk prostate cancer that could be used to personalize therapy, given that consensus guidelines recommend similar treatments for all radiation-managed patients with high-risk disease. Methods and Materials: We studied 3618 patients with cT1-T3aN0M0 high-risk or unfavorable intermediate-risk prostate adenocarcinoma treated with radiation at a single institution between 1997 and 2013. Favorable high-risk was defined as T1c disease with either Gleason 4 + 4 = 8 and prostate-specific antigen <10 ng/mL or Gleason 6 and prostate-specific antigen >20 ng/mL. Competing risks regression was used to determine differences in the risk of prostate cancer–specific mortality (PCSM) after controlling for baseline factors and treatment. Our results were validated in a cohort of 13,275 patients using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Results: Patients with favorable high-risk disease had significantly better PCSM than other men with high-risk disease (adjusted hazard ratio [AHR] 0.42, 95% confidence interval [CI] 0.18-0.996, P=.049) and similar PCSM as men with unfavorable intermediate-risk disease (AHR 1.17, 95% CI 0.50-2.75, P=.710). We observed very similar results within the SEER-Medicare cohort (favorable high-risk vs other high-risk: AHR 0.21, 95% CI 0.11-0.41, P<.001; favorable high-risk vs unfavorable intermediate-risk: AHR 0.67, 95% CI 0.33-1.36, P=.268). Conclusions: Patients with favorable high-risk prostate cancer have significantly better PCSM than other patients with high-risk disease and similar PCSM as those with unfavorable intermediate-risk disease, who are typically treated with shorter-course androgen deprivation therapy. This new classification system may allow for personalization of treatment within high-risk disease, such as consideration of shorter-course androgen deprivation therapy for favorable high-risk disease.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Serum biomarkers for diagnosis and prediction of type 1 diabetes

Type 1 diabetes (T1D) culminates in the autoimmune destruction of the pancreatic ß-cells, leading to insufficient production of insulin and development of hyperglycemia. Serum biomarkers including glucose, glycated molecules, c-peptide, and autoantibodies have been well established to diagnose T1D from other subtypes of diabetes. However, these molecules often mark a late stage of the disease when ~90% of the pancreatic insulin-producing ß-cells have already been lost. With the prevalence of T1D increasing worldwide and because of the physical and psychological burden induced by this disease, there is a great need for prognostic biomarkers to predict T1D development or progression. This would allow us to identify individuals at high risk for early prevention and intervention. Therefore, considerable efforts have been dedicated to the understanding of disease etiology and the discovery of novel biomarkers in the last few decades. The advent of high-throughput and sensitive ‘-omics’ technologies for the study of proteins, nucleic acids, and metabolites have allowed large scale profiling of protein expression and gene changes in T1D patients relative to disease-free controls. In this review, we briefly discuss the classical diagnostic biomarkers of T1D and mainly focus on the novel biomarkers that are identified as markers of ß-cell destruction and screened with the use of state-of-the-art ‘-omics’ technologies.

Yi, Lian↗
DOE OSTI2020

Adaptive Recovery Model: Designing Systems for Testing Tracing and Vaccination to Support COVID-19 Recovery Planning.

This report documents a new approach to designing disease control policies that allocate scarce testing, contact tracing, and vaccination resources to better control community transmission of COVID19 or similar diseases. The Adaptive Recovery Model (ARM) combines a deterministic compartmental disease model with a stochastic network disease propagation model to enable us to simulate COVID-19 community spread through the lens of two complementary modeling motifs. ARM contact networks are derived from cell-phone location data that have been anonymized and interpreted as individual arrivals to specic public locations. Modeling disease spread over these networks allows us to identify locations within communities conducive to rapid disease spread. ARM applies this model- and data-derived abstractions of community transmission to evaluate the effectiveness of disease control measures including targeted social distancing, contact tracing, testing and vaccination. The architecture of ARM provides a unique capacity to help decision makers understand how best to deploy scarce testing, tracing and vaccination resources to minimize disease-spread potential in a community. This document details the novel mathematical formulations underlying ARM, presents a dynamical stability analysis of the deterministic model components, a sensitivity analysis of control parameters and network structure, and summarizes a process for deriving contact networks from cell-phone location data. An example use case steps through applying ARM to evaluate three targeted social distancing policies using Bernalillo County, New Mexico as an exemplar test locale. This step-by-step analysis demonstrates how ARM can be used to measure the relative performance of competing public health policies. Initial scenario tests of ARM shows that ARMs design focus on resource utilization rather than simple incidence prediction can provide decision makers with additional quantitative guidance for managing ongoing public health emergencies and planning future responses.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗
DOE OSTI2022

Editorial: Nanotechnology for natural products

Humans around the globe have lived through an unprecedented time. The emergence and rapid spread of coronavirus disease 2019 (COVID-19) have resulted in the loss of millions of lives, and this number is still climbing every day and hour. As a consequence, there have been drastic changes over the past two years in how we live, communicate, and work, some of which may have changed forever: remote conferencing has become a new norm for businesses, schools, and academia; work-from-home and hybrid working is now more than just acceptable in many industries; most importantly, COVID-19 has raised global awareness of infectious diseases and pandemic responses to an exceptional level. Certainly, COVID-19 is not the only disease that is causing human suffering at this moment. Other highly contagious and lethal viruses, such as the human immunodeficiency virus (HIV), Ebola, and the recent addition to the list, Monkeypox, pose extraordinary challenges to modern civilizations. On the other hand, non-communicable diseases, such as heart disease, stroke, and cancer, are still claiming the majority of deaths on a global level (World Health Organization, 2020). Before the availability of synthetic drugs, civilizations worldwide relied on natural products extracted from the environment and various organisms for healthcare. Natural products and their derivatives continue to be critical components in the drug library available today. Indeed, almost a quarter of the new drugs approved by the US Food and Drug Administration (FDA) since 1981 are natural products, botanical mixtures, or their derivatives (Newman and Cragg, 2020). Recent developments in analytical characterization, genome mining, and engineering have further increased interest in drug discovery from the pool of natural products (Atanasov et al., 2021). This Research Topic celebrates a collection of studies at the intersection of natural product research and nanotechnological advances. As a successor and extension of the Research Topic in “Nanotechnology in Traditional Medicines and Natural Products” published last year (Zhang et al., 2021), the present collection focused more on recent developments in employing the synthesis and characterization of nanostructures for the delivery of functional natural products. Specifically, the use of carrier nanostructures to conjugate or encapsulate therapeutically active natural products with carrier nanostructures could enable their robust, targeted delivery tailored to either tackle a specific disease or unlock a drug administration pathway. Over the last decade, nanostructures such as liposomes (Pattni et al., 2015) and lipid nanoparticles (Hou et al., 2021) have been developed as versatile platforms for the inclusion and delivery of a wide range of therapeutical compounds; a significant advance in this aspect is the stabilization of mRNA strands for COVID-19 vaccination recently produced by Pfizer/BioNTech and Moderna (Tenchov et al., 2021). Such engineered nanomaterials are now widely used in the development of new drugs, while regulatory forces, such as the US FDA, remain cautious with the evaluation of each product on a case-by-case basis (Wang and Grainger, 2022). In this collection, Zeng et al. provided a timely review of natural products conjugated to and contained within nanomaterials for the ongoing COVID-19 pandemic. Natural products that are potentially useful in the mitigation of this disease, such as chloroquine and curcumin, supported in nanocarrier systems, have been discussed in detail. More broadly, Cheng et al. comprehensively reviewed the use of liposomes as a nanocarrier for natural products. This article provides a summary of natural product compounds and extracts used to form liposomal structures. Readers can further enjoy the practical aspects of these engineered drugs for the treatment of specific diseases as well as insights into future directions in this field.

peptides↗
NASA NTRS1998

MAPS of Cancer

Our goal was to produce an interactive visualization from a mathematical model that successfully predicts metastases from head and neck cancer. We met this goal early in the project. The visualization is available for the public to view. Our work appears to fill a need for more information about this deadly disease. The idea of this project was to make an easily interpretable visualization based on what we call "functional maps" of disease. A functional map is a graphic summary of medical data, where distances between parts of the body are determined by the probability of disease, not by anatomical distances. Functional maps often beat little resemblance to anatomical maps, but they can be used to predict the spread of disease. The idea of modeling the spread of disease in an abstract multidimensional space is difficult for many people. Our goal was to make the important predictions easy to see. NASA must face this problem frequently: how to help laypersons and professionals see important trends in abstract, complex data. We took advantage of concepts perfected in NASA's graphics libraries. As an analogy, consider a functional map of early America. Suppose we choose travel times, rather than miles, as our measures of inter-city distances. For Abraham Lincoln, travel times would have been the more meaningful measure of separation between cities. In such a map New Orleans would be close to Memphis because of the Mississippi River. St. Louis would be close to Portland because of the Oregon Trail. Oklahoma City would be far from Little Rock because of the Cheyenne. Such a map would look puzzling to those of us who have always seen physical maps, but the functional map would be more useful in predicting the probabilities of inter-site transit. Continuing the analogy, we could predict the spread of social diseases such as gambling along the rivers and cattle rustling along the trails. We could simply print the functional map of America, but it would be more interesting to show meaningful patterns of dispersal. We had previously published the functional map of the head and neck, but it was difficult to explain to either patients or surgeons because that view of our body did not resemble anatomy. This discrepancy between functional and physical maps is just a mathematical restatement of the well-known fact that some diseases, such as head and neck cancer, spread in complex patterns, not always to the next nearest site. We had discovered that a computer could re-arrange anatomy so that this particular disease spreads to the next nearest site. The functional map explains over 95% of the metastases in 1400 patients. In a sense, we had graphed what our body "looks like" to a tumor. The tumor readily travels between adjacent areas in the functional map. The functional map is a succinct visual display of trends that are not easily appreciated in tables of probabilities.

Gray, Lincoln↗
NASA NTRS2001

Neuroprotection for the new millennium. Matchmaking pharmacology and technology

A major theme of the 1990s in the pathophysiology of nervous system injury has been the multifactorial etiology of irreversible injury. Multiple causes imply multiple opportunities for therapeutic intervention--hence the abandonment of the "magic bullet" single pharmacologic agent for neuroprotection in favor of pharmacologic "cocktails". A second theme of the 1990s has been the progress in technology for neuroprotection, minimally- or non-invasive monitoring as well as treatment. Cardiac stenting has eliminated the need, in many cases, for open heart surgery; deep brain stimulation for Parkinson's disease has offered significant improvement in quality of life for many who had exhausted cocktail drug treatment for their disease. Deep brain stimulation of the subthalamic nucleus offers a novel treatment for Parkinson's disease where a technological advance may actually be an intervention with effects that are normally expected from pharmacologic agents. Rather than merely "jamming" the nervous system circuits involved in Parkinson's disease, deep brain stimulation of the subthalamic nucleus appears to improve the neurotransmitter imbalance that lies at the heart of Parkinson's disease. It may also slow the progression of the disease. Given the example of deep brain stimulation of the subthalamic nucleus for Parkinson's disease, in future one may expect other technological or "hardware" interventions to influence the programming or "software" of the nervous system's physiologic response in certain disease states.

Review Literature↗
DOE OSTI2019

The Cardiorenal Axis: Myocardial Perfusion, Metabolism, and Innervation

Purpose of the Review: Cardiorenal syndrome (CRS), defined as concomitant heart and kidney disease, has been a focus of attention for nearly a decade. As more patients survive severe acute and chronic heart and kidney diseases, CRS has emerged as an “epidemic” of modern medicine. Significant advances have been made in unraveling the complex mechanisms that underlie CRS based on classification of the condition into five pathophysiologic subtypes. In types 1 and 2, acute or chronic heart disease results in renal dysfunction, while in types 3 and 4, acute or chronic kidney diseases are the inciting factors for heart disease. Type 5 CRS is defined as concomitant heart and kidney dysfunction as part of a systemic condition such as sepsis or autoimmune disease. Recent Findings: There are ongoing efforts to better define subtypes of CRS based on historical information, clinical manifestations, laboratory data (including biomarkers), and imaging characteristics. Systematic evaluation of CRS by advanced cardiac imaging, however, has been limited in scope and mostly focused on type 4 CRS. This is in part related to lack of clinical trials applying advanced cardiac imaging in the acute setting and exclusion of patients with significant renal disease from studies of such techniques in chronic HF. Summary: Advanced cardiac nuclear imaging is well poised for assessment of the pathophysiology of CRS by offering a myriad of molecular probes without the need for nephrotoxic contrast agents. In this review, we examine the current or potential future application of advanced cardiac imaging to evaluation of myocardial perfusion, metabolism, and innervation in patients with CRS.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma in the Modern Era

Purpose: To analyze treatment outcomes for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) at a single institution. Patients and Methods: Patients with newly diagnosed NLPHL between 1996 and 2013 were reviewed retrospectively. Patients treated before 1996 were excluded because the majority received extended field radiation therapy (RT) alone. Results: Fifty-five patients (22 ≤ 21 years old) were identified. The median follow-up time was 6.8 years. Among 37 patients with limited-stage (I-II) disease, treatments included involved field RT at a median dose of 36 Gy (n=9), rituximab monotherapy (n=9), observation (n=3), and response-adaptive therapy (n=16), in which the RT dose was reduced from 25.5 Gy to 15 Gy or was eliminated based on interim imaging after chemotherapy. The 5-year progression-free survival (PFS) was 76.4% (95% confidence interval [CI], 63.1-92.4). Nine patients experienced progression, including 5 receiving rituximab, 2 undergoing observation, and 2 receiving response-adaptive therapy. Rituximab was associated with an inferior PFS compared with RT alone (P=.02). The difference in PFS between response-adaptive therapy and RT alone was not statistically significant (P=.39). Among 18 patients with advanced-stage (III-IV) disease, treatments included chemotherapy alone (n=3), combined modality therapy (CMT) (n=2), response-adaptive therapy (n=2), rituximab (n=7), and observation (n=4). The 5-year PFS was 29.9% (CI, 13.3-67.4). Twelve patients experienced progression, including 1 receiving chemotherapy, 1 receiving CMT, 6 receiving rituximab, and 4 undergoing observation. There was no significant PFS difference between rituximab and non-rituximab therapies (P=.19) within the caveat of small sample sizes. In the entire cohort, 9 patients (3 with limited disease, 6 with advanced disease) experienced large cell transformation (LCT). Seven patients died; of those, 5 died with LCT. Conclusions: For limited disease, response-adaptive therapy demonstrated comparable outcomes with RT alone. Rituximab monotherapy resulted in inferior outcomes for limited disease and a high relapse rate for advanced disease.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Biodiversity and Global Health: Intersection of Health, Security, and the Environment

One of the biggest consequences of large-scale environmental change is the loss of biodiversity. Recent studies predict a loss of 1 million species in the near future. Biodiversity loss and land use change through anthropogenic disturbance are known to affect disease exposure, disease severity, and disease impacts. It is becoming increasingly clear that biodiversity loss will lead to an increase in infectious diseases in certain regions. Changes in biodiversity may contain important signatures for prediction of infectious diseases and outbreaks. Here, we argue that areas of high or rapid biodiversity loss will be critical to monitor under the umbrella of global health security. Global Health Security consists of the actions and activities required to reduce the impact of public health events in populations living in different geographic regions and across international borders. Like infectious diseases, climate change and other causes of environmental changes do not respect international borders and are becoming more widespread in all parts of the world. Here, the relationships among biodiversity, climate and environmental changes, and pathogen prevalence are dynamic, context dependent, and complex. Accounting for this complexity requires the inclusion of the environment sector, presently missing, when evaluating the potential of global health security actions for mitigating disease risks.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

Framework for 3D histologic reconstruction and fusion with in vivo MRI: Preliminary results of characterizing pulmonary inflammation in a mouse model

Purpose: Pulmonary inflammation is associated with a variety of diseases. Assessing pulmonary inflammation on in vivo imaging may facilitate the early detection and treatment of lung diseases. Although routinely used in thoracic imaging, computed tomography has thus far not been compellingly shown to characterize inflammation in vivo. Alternatively, magnetic resonance imaging (MRI) is a nonionizing radiation technique to better visualize and characterize pulmonary tissue. Prior to routine adoption of MRI for early characterization of inflammation in humans, a rigorous and quantitative characterization of the utility of MRI to identify inflammation is required. Such characterization may be achieved by considering ex vivo histology as the ground truth, since it enables the definitive spatial assessment of inflammation. In this study, the authors introduce a novel framework to integrate 2D histology, ex vivo and in vivo imaging to enable the mapping of the extent of disease from ex vivo histology onto in vivo imaging, with the goal of facilitating computerized feature analysis and interrogation of disease appearance on in vivo imaging. The authors’ framework was evaluated in a preclinical preliminary study aimed to identify computer extracted features on in vivo MRI associated with chronic pulmonary inflammation. Methods: The authors’ image analytics framework first involves reconstructing the histologic volume in 3D from individual histology slices. Second, the authors map the disease ground truth onto in vivo MRI via coregistration with 3D histology using the ex vivo lung MRI as a conduit. Finally, computerized feature analysis of the disease extent is performed to identify candidate in vivo imaging signatures of disease presence and extent. Results: The authors evaluated the framework by assessing the quality of the 3D histology reconstruction and the histology—MRI fusion, in the context of an initial use case involving characterization of chronic inflammation in a mouse model. The authors’ evaluation considered three mice, two with an inflammation phenotype and one control. The authors’ iterative 3D histology reconstruction yielded a 70.1% ± 2.7% overlap with the ex vivo MRI volume. Across a total of 17 anatomic landmarks manually delineated at the division of airways, the target registration error between the ex vivo MRI and 3D histology reconstruction was 0.85 ± 0.44 mm, suggesting that a good alignment of the ex vivo 3D histology and ex vivo MRI had been achieved. The 3D histology-in vivo MRI coregistered volumes resulted in an overlap of 73.7% ± 0.9%. Preliminary computerized feature analysis was performed on an additional four control mice, for a total of seven mice considered in this study. Gabor texture filters appeared to best capture differences between the inflamed and noninflamed regions on MRI. Conclusions: The authors’ 3D histology reconstruction and multimodal registration framework were successfully employed to reconstruct the histology volume of the lung and fuse it with in vivo MRI to create a ground truth map for inflammation on in vivo MRI. The analytic platform presented here lays the framework for a rigorous validation of the identified imaging features for chronic lung inflammation on MRI in a large prospective cohort.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Dexamethasone treatment did not exacerbate Seneca Valley virus infection in nursery-age pigs

Background: Senecavirus A, commonly known as Seneca Valley virus (SVV), is a picornavirus that has been infrequently associated with porcine idiopathic vesicular disease (PIVD). In late 2014 there were multiple PIVD outbreaks in several states in Brazil and samples from those cases tested positive for SVV. Beginning in July of 2015, multiple cases of PIVD were reported in the United States in which a genetically similar SVV was also detected. These events suggested SVV could induce vesicular disease, which was recently demonstrated with contemporary US isolates that produced mild disease in pigs. It was hypothesized that stressful conditions may exacerbate the expression of clinical disease and the following experiment was performed. Two groups of 9-week-old pigs were given an intranasal SVV challenge with one group receiving an immunosuppressive dose of dexamethasone prior to challenge. After challenge animals were observed for the development of clinical signs and serum and swabs were collected to study viral shedding and antibody production. In addition, pigs were euthanized 2, 4, 6, 8, and 12 days post inoculation (dpi) to demonstrate tissue distribution of virus during acute infection. Results: Vesicular disease was experimentally induced in both groups with the duration and magnitude of clinical signs similar between groups. During acute infection [0–14 days post infection (dpi)], SVV was detected by PCR in serum, nasal swabs, rectal swabs, various tissues, and in swabs from ruptured vesicles. From 15 to 30 dpi, virus was less consistently detected in nasal and rectal swabs, and absent from most serum samples. Virus neutralizing antibody was detected by 5 dpi and lasted until the end of the study. Conclusion: Treatment with an immunosuppressive dose of dexamethasone did not drastically alter the clinical disease course of SVV in experimentally infected nursery aged swine. A greater understanding of SVV pathogenesis and factors that could exacerbate disease can help the swine industry with control and prevention strategies directed against this virus.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Imaging in the pre-operative staging of ovarian cancer

The main prognostic factor in ovarian cancer is the stage of disease at diagnosis. The staging system in use (FIGO classification, updated in 2014) is based on the surgical-pathological findings. Although surgical staging is the gold standard in ovarian cancer, the initial patient management depends on the imaging-based pre-surgical staging assessment, in order to identify unresectable or difficult to resect disease. Radiologists need to be aware of the strengths of the available imaging modalities, as well as the imaging pitfalls. Clear understanding of pattern of disease spread and review areas are critical for accurate staging and treatment planning. The current standard of care for pre-surgical staging is CT of the thorax, abdomen, and pelvis. This allows a rapid evaluation of disease extent and is fairly accurate in identifying bulky disease but has definite limitations in assessing the extent of small volume disease and in the confirmation of certain sites of disease beyond the abdomen. Functional MRI has been reported to be superior in detecting small peritoneal deposits. PET/CT may be used as a problem-solving tool in some patients where determination remains unclear, particularly in confirmation of advanced stage beyond the abdomen.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

PET imaging of glucose and fatty acid metabolism for NAFLD patients

The study presented in this issue of the Journal by Tang and colleagues illuminate the deficiency in our knowledge of the reciprocal metabolic relationship between liver and heart in health and disease. The results presented in this paper used a large number of previously acquired 18 F-FDG PET studies to investigate the association between non-alcoholic fatty liver disease (NAFLD) (Figure 1A) and myocardial glucose uptake. Previous work published by Lee and colleagues in Metabolism, had found a significant correlation between NAFLD and vascular inflammation using 18 F-FDG PET to measure maximum target-to-background uptake in the carotid arteries; however, the present study is the first to elicit through imaging the correlation between NAFLD and potential cardiac metabolic abnormalities. Patients with NAFLD have a high risk of related cardiovascular disease (CVD). It has been pointed out that the leading cause of death in NAFLD patients is CVD rather than liver-associated complications, of which only 5% of NAFLD patients die from liver-related diseases. 18 F-FGD PET is an important indicator of cardiac glucose metabolism and its alteration in the presence of disease; however, to systematically understand the relation between NAFLD and the risk of cardiovascular disease, other probes, in addition to 18 FDG, should be used to study the complex and dynamic pathways of energy substrate metabolism in the heart in health and disease and their relationship to the metabolic pathways of other body organs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2012

Unilateral Radiotherapy for the Treatment of Tonsil Cancer

Purpose: To assess, through a retrospective review, clinical outcomes of patients with squamous cell carcinoma of the tonsil treated at the M. D. Anderson Cancer Center with unilateral radiotherapy techniques that irradiate the involved tonsil region and ipsilateral neck only. Methods and Materials: Of 901 patients with newly diagnosed squamous cell carcinoma of the tonsil treated with radiotherapy at our institution, we identified 102 that were treated using unilateral radiotherapy techniques. All patients had their primary site of disease restricted to the tonsillar fossa or anterior pillar, with <1 cm involvement of the soft palate. Patients had TX (n = 17 patients), T1 (n = 52), or T2 (n = 33) disease, with Nx (n = 3), N0 (n = 33), N1 (n = 23), N2a (n = 21), or N2b (n = 22) neck disease. Results: Sixty-one patients (60%) underwent diagnostic tonsillectomy before radiotherapy. Twenty-seven patients (26%) underwent excision of a cervical lymph node or neck dissection before radiotherapy. Median follow-up for surviving patients was 38 months. Locoregional control at the primary site and ipsilateral neck was 100%. Two patients experienced contralateral nodal recurrence (2%). The 5-year overall survival and disease-free survival rates were 95% and 96%, respectively. The 5-year freedom from contralateral nodal recurrence rate was 96%. Nine patients required feeding tubes during therapy. Of the 2 patients with contralateral recurrence, 1 experienced an isolated neck recurrence and was salvaged with contralateral neck dissection only and remains alive and free of disease. The other patient presented with a contralateral base of tongue tumor and involved cervical lymph node, which may have represented a second primary tumor, and died of disease. Conclusions: Unilateral radiotherapy for patients with TX-T2, N0-N2b primary tonsil carcinoma results in high rates of disease control, with low rates of contralateral nodal failure and a low incidence of acute toxicity requiring gastrostomy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Can Locoregional Treatment of the Primary Tumor Improve Outcomes for Women With Stage IV Breast Cancer at Diagnosis?

Purpose: To examine the effect of locoregional treatment (LRT) of the primary tumor on survival in patients with Stage IV breast cancer at diagnosis. Methods and Materials: The study cohort comprised 733 women referred to the British Columbia Cancer Agency between 1996 and 2005 with newly diagnosed clinical or pathologic M1 breast cancer. Tumor and treatment characteristics, overall survival (OS), and locoregional progression-free survival were compared between patients treated with (n = 378) and without (n = 355) LRT of the primary disease. Multivariable analysis was performed with Cox regression modeling. Results: The median follow-up time was 1.9 years. LRT consisted of surgery alone in 67% of patients, radiotherapy alone in 22%, and both in 11%. LRT was used more commonly in women with age <50 years, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, Stage T1-2 tumors, N0-1 disease, limited M1 burden, and asymptomatic M1 disease (all p < 0.05). Systemic therapy was used in 92% of patients who underwent LRT and 85% of patients who did not. In patients treated with LRT compared with those without LRT, the 5-year OS rates were 21% vs. 14% (p < 0.001), and the rates of locoregional progression-free survival were 72% vs. 46% (p < 0.001). Among 378 patients treated with LRT, the rates of 5-year OS were higher in patients with age <50, ECOG performance status 0-1, estrogen receptor-positive disease, clear surgical margins, single subsite, bone-only metastasis, and one to four metastatic lesions (all p < 0.003). On multivariable analysis, LRT was associated with improved OS (hazard ratio, 0.78; 95% confidence interval, 0.64-0.94, p = 0.009). Conclusion: Locoregional treatment of the primary disease is associated with improved survival in some women with Stage IV breast cancer at diagnosis. Among those treated with LRT, the most favorable rates of survival were observed in subsets with young age, good performance status, estrogen receptor-positive disease, clear margins, and distant disease limited to one subsite, bone-only involvement, or fewer than five metastatic lesions.

62 RADIOLOGY AND NUCLEAR MEDICINE↗