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2. Assessing Parameterized Geometric Models of Woven Composites using Image-Based Simulations

Author

Foster, Collin W., Collins, Lincoln N., Panerai, Francesco, and Roberts, Scott A.

Subjects
Condensed Matter - Materials Science
Abstract

Mesoscale simulations of woven composites using parameterized analytical geometries offer a way to connect constituent material properties and their geometric arrangement to effective composite properties and performance. However, the reality of as-manufactured materials often differs from the ideal, both in terms of tow geometry and manufacturing heterogeneity. As such, resultant composite properties may differ from analytical predictions and exhibit significant local variations within a material. We employ mesoscale finite element method simulations to compare idealized analytical and as-manufactured woven composite materials and study the sensitivity of their effective properties to the mesoscale geometry. Three-dimensional geometries are reconstructed from X-ray computed tomography, image segmentation is performed using deep learning methods, and local fiber orientation is obtained using the structure tensor calculated from image scans. Suitable approximations to composite properties, using analytical unit cell calculations and effective media theory, are assessed. Our findings show that an analytical geometry and sub-unit cell geometry provide reasonable predictions for the effective thermal properties of a multi-layer production composite.

Published
2023

3. CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer.

Author

Faraoni, Erika Y, Singh, Kanchan, Chandra, Vidhi, Le Roux, Olivereen, Dai, Yulin, Sahin, Ismet, O'Brien, Baylee J, Strickland, Lincoln N, Li, Le, Vucic, Emily, Warner, Amanda N, Pruski, Melissa, Clark, Trent, Van Buren, George, Thosani, Nirav C, Bynon, John S, Wray, Curtis J, Bar-Sagi, Dafna, Poulsen, Kyle L, Vornik, Lana A, Savage, Michelle I, Sei, Shizuko, Mohammed, Altaf, Zhao, Zhongming, Brown, Powel H, Mills, Tingting, Eltzschig, Holger K, McAllister, Florencia, and Bailey-Lundberg, Jennifer M

Subjects
Animals, Humans, Mice, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, 5'-Nucleotidase, Adenosine, Cancer Vaccines, Immunotherapy, Tumor Microenvironment, Immunosuppression Therapy, Pancreatic Cancer, Cancer, Rare Diseases, Genetics, Digestive Diseases, 5.1 Pharmaceuticals, Aetiology, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin-dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by IHC and high-performance liquid chromatography. Analysis in human PDAC subtypes indicated that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC squamous and basal subtypes, considered to have the highest immunosuppression and worst prognosis. Multiplex immunofluorescent analysis showed that activated CD8+ T cells in the PDAC tumor microenvironment express high levels of CD73, indicating an opportunity for immunotherapeutic targeting. Delivery of CD73 small-molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. In addition, the adenosine receptor Adora2b was a determinant of adenosine-mediated immunosuppression in PDAC. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment elevated in the ductal cell of origin, linking biology with subtype classification, critical components for PDAC immunoprevention and personalized approaches for immunotherapeutic intervention.SignificanceDuctal-derived pancreatic tumors have elevated epithelial and CD8+GZM+ T-cell CD73 expression that confers sensitivity to small-molecule inhibition of CD73 or Adora2b to promote CD8+ T-cell-mediated tumor regression. See related commentary by DelGiorno, p. 977.

Published
2023

4. A Single-Cell Atlas of the Murine Pancreatic Ductal Tree Identifies Novel Cell Populations With Potential Implications in Pancreas Regeneration and Exocrine Pathogenesis

Author

Fernández, Ángel, Casamitjana, Joan, Holguín-Horcajo, Adrián, Coolens, Katarina, Mularoni, Loris, Guo, Li, Hartwig, Olga, Düking, Tim, Vidal, Noemi, Strickland, Lincoln N., Pasquali, Lorenzo, Bailey-Lundberg, Jennifer M., Rooman, Ilse, Wang, Yue J., and Rovira, Meritxell

Published
2024
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5. Mesoscale simulation of woven composite design decisions

Author

Collins, Lincoln N. and Roberts, Scott A.

Subjects
Computer Science - Computational Engineering, Finance, and Science
Abstract

Characterizing the connection between material design decisions/parameters and their effective properties allows for accelerated materials development and optimization. We present a global sensitivity analysis of woven composite thermophysical properties, including density, volume fraction, thermal conductivity, specific heat, moduli, permeability, and tortuosity, predicted using mesoscale finite element simulations. The mesoscale simulations use microscale approximations for the tow and matrix phases. We performed Latin hypercube sampling of viable input parameter ranges, and the resulting effective property distributions are analyzed using a surrogate model to determine the correlations between material parameters and responses, interactions between properties, and finally Sobol' indices and sensitivities. We demonstrate that both constituent physical properties and the mesoscale geometry strongly influence the composite material properties.

Published
2021

6. Quantifying the unknown impact of segmentation uncertainty on image-based simulations

Author

Krygier, Michael C., LaBonte, Tyler, Martinez, Carianne, Norris, Chance, Sharma, Krish, Collins, Lincoln N., Mukherjee, Partha P., and Roberts, Scott A.

Subjects
Computer Science - Computational Engineering, Finance, and Science, Electrical Engineering and Systems Science - Image and Video Processing
Abstract

Image-based simulation, the use of 3D images to calculate physical quantities, fundamentally relies on image segmentation to create the computational geometry. However, this process introduces image segmentation uncertainty because there is a variety of different segmentation tools (both manual and machine-learning-based) that will each produce a unique and valid segmentation. First, we demonstrate that these variations propagate into the physics simulations, compromising the resulting physics quantities. Second, we propose a general framework for rapidly quantifying segmentation uncertainty. Through the creation and sampling of segmentation uncertainty probability maps, we systematically and objectively create uncertainty distributions of the physics quantities. We show that physics quantity uncertainty distributions can follow a Normal distribution, but, in more complicated physics simulations, the resulting uncertainty distribution can be both nonintuitive and surprisingly nontrivial. We also establish that simply bounding the uncertainty can fail in situations that are sensitive to image segmentation. While our work does not eliminate segmentation uncertainty, it makes visible the previously unrecognized range of uncertainty currently plaguing image-based simulation, enabling more credible simulations.

Published
2020
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8. The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer

Author

Lincoln N. Strickland, Erika Y. Faraoni, Wei Ruan, Xiaoyi Yuan, Holger K. Eltzschig, and Jennifer M. Bailey-Lundberg

Subjects
immunotherapy, pancreatic adenocarcinoma, hypoxia, Adenosine receptor 2B, CD8+ T cell response, Immunologic diseases. Allergy, RC581-607
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma that impedes drug delivery, reduces parenchymal blood flow, and suppresses the anti-tumor immune response. The extracellular matrix and abundance of stromal cells result in severe hypoxia within the tumor microenvironment (TME), and emerging publications evaluating PDAC tumorigenesis have shown the adenosine signaling pathway promotes an immunosuppressive TME and contributes to the overall low survival rate. Hypoxia increases many elements of the adenosine signaling pathway, resulting in higher adenosine levels in the TME, further contributing to immune suppression. Extracellular adenosine signals through 4 adenosine receptors (Adora1, Adora2a, Adora2b, Adora3). Of the 4 receptors, Adora2b has the lowest affinity for adenosine and thus, has important consequences when stimulated by adenosine binding in the hypoxic TME. We and others have shown that Adora2b is present in normal pancreas tissue, and in injured or diseased pancreatic tissue, Adora2b levels are significantly elevated. The Adora2b receptor is present on many immune cells, including macrophages, dendritic cells, natural killer cells, natural killer T cells, γδ T cells, B cells, T cells, CD4+ T cells, and CD8+ T cells. In these immune cell types, adenosine signaling through Adora2b can reduce the adaptive anti-tumor response, augmenting immune suppression, or may contribute to transformation and changes in fibrosis, perineural invasion, or the vasculature by binding the Adora2b receptor on neoplastic epithelial cells, cancer-associated fibroblasts, blood vessels, lymphatic vessels, and nerves. In this review, we discuss the mechanistic consequences of Adora2b activation on cell types in the tumor microenvironment. As the cell-autonomous role of adenosine signaling through Adora2b has not been comprehensively studied in pancreatic cancer cells, we will also discuss published data from other malignancies to infer emerging therapeutic considerations for targeting the Adora2b adenosine receptor to reduce the proliferative, invasive, and metastatic potential of PDAC cells.

Published
2023
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10. Radiofrequency ablation in combination with CD73 inhibitor AB680 reduces tumor growth and enhances anti-tumor immunity in a syngeneic model of pancreatic ductal adenocarcinoma

Author

Erika Y. Faraoni, Lincoln N. Strickland, Baylee J. O’Brien, Joseph F. Barraza, Nirav C. Thosani, Curtis J. Wray, Tingting W. Mills, and Jennifer M. Bailey-Lundberg

Subjects
pancreatic cancer, CD73, adenosine, AB680, inosine, radiofrequency ablation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Pancreatic ductal adenocarcinoma presents a 5-year overall survival rate of 11%, placing an imperative need for the discovery and application of innovative treatments. Radiofrequency ablation represents a promising therapy for PDA, as studies show it induces coagulative necrosis and a host adaptive immune response. In this work we evaluated the effects of RFA treatment in vivo by establishing a syngeneic mouse model of PDA and performing tumor ablation in one flank. Our studies revealed RFA acutely impaired PDA tumor growth; however, such effects were not sustained one week after treatment. Adenosine (ADO) pathway represents a strong immunosuppressive mechanism that was shown to play a role in PDA progression and preliminary data from ongoing clinical studies suggest ADO pathway inhibition may improve therapeutic outcomes. Thus, to investigate whether ADO generation may be involved in tumor growth relapse after RFA, we evaluated adenosine-monophosphate (AMP), ADO and inosine (INO) levels by HPLC and found they were acutely increased after treatment. Thus, we evaluated an in vivo CD73 inhibition in combination with RFA to study ADO pathway implication in RFA response. Results showed combination therapy of RFA and a CD73 small molecule inhibitor (AB680) in vivo promoted sustained tumor growth impairment up to 10 days after treatment as evidenced by increased necrosis and anti-tumor immunity, suggesting RFA in combination with CD73 inhibitors may improve PDA patient response.

Published
2022
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13. Multi agent control for space based interferometry

Author

Lincoln, N. K. and Veres, Sandor

Subjects
620, QA75 Electronic computers. Computer science, TL Motor vehicles. Aeronautics. Astronautics
Abstract

Agent systems have been accepted and used advantageously by computer scientists since their inception, but such systems have not been used so readily within the realms of control engineering or robotics. The work contained within this thesis investigates separated spacecraft interferometry in the context of a multi-agent system, under the influence of libration point orbital dynamics. The main focus is on the development of key agent skills, including state estimation, guidance, control and decision methods to attain the desired system output; within the consideration of decision methods, a comparison between centralized and distributed decisions is made. Whilst mainly focussing on the development of these skills, additional considerations pertinent to agent system development are also discussed. A discrete time control method, integrating Kalman filtering with sliding mode control and using potential function guidance to achieve velocity tracking with six degrees of freedom, is developed for the purposes of controlling agent motion. Whilst developed for the purposes of spacecraft agent control, the presented methods are equally valid to any other vehicular agent system such as UAVs or AUVs if considering inter-agent regulation. Centralized and distributed decision methods are developed to enable appropriate autonomous actions to be performed by the agent system. Primarily these actions include selective attainment and regulation of a non-natural orbits relative to a central agent to form an appropriate array configuration and instances of array reconfiguration to compensate for both failed agents and to maximize the mission duration.

Published
2009

14. CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer

Author

Erika Y. Faraoni, Kanchan Singh, Vidhi Chandra, Olivereen Le Roux, Yulin Dai, Ismet Sahin, Baylee J. O'Brien, Lincoln N. Strickland, Le Li, Emily Vucic, Amanda N. Warner, Melissa Pruski, Trent Clark, George Van Buren, Nirav C. Thosani, John S. Bynon, Curtis J. Wray, Dafna Bar-Sagi, Kyle L. Poulsen, Lana A. Vornik, Michelle I. Savage, Shizuko Sei, Altaf Mohammed, Zhongming Zhao, Powel H. Brown, Tingting Mills, Holger K. Eltzschig, Florencia McAllister, and Jennifer M. Bailey-Lundberg

Subjects
Immunosuppression Therapy, Cancer Research, Adenosine, Carcinoma, Oncology and Carcinogenesis, Cancer Vaccines, Pancreatic Neoplasms, Mice, Pancreatic Cancer, Rare Diseases, Oncology, Pancreatic Ductal, 5.1 Pharmaceuticals, Tumor Microenvironment, Genetics, Animals, Humans, 2.1 Biological and endogenous factors, Immunotherapy, Oncology & Carcinogenesis, Aetiology, Development of treatments and therapeutic interventions, Digestive Diseases, 5'-Nucleotidase, Cancer
Abstract

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin–dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by IHC and high-performance liquid chromatography. Analysis in human PDAC subtypes indicated that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC squamous and basal subtypes, considered to have the highest immunosuppression and worst prognosis. Multiplex immunofluorescent analysis showed that activated CD8+ T cells in the PDAC tumor microenvironment express high levels of CD73, indicating an opportunity for immunotherapeutic targeting. Delivery of CD73 small-molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. In addition, the adenosine receptor Adora2b was a determinant of adenosine-mediated immunosuppression in PDAC. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment elevated in the ductal cell of origin, linking biology with subtype classification, critical components for PDAC immunoprevention and personalized approaches for immunotherapeutic intervention. Significance: Ductal-derived pancreatic tumors have elevated epithelial and CD8+GZM+ T-cell CD73 expression that confers sensitivity to small-molecule inhibition of CD73 or Adora2b to promote CD8+ T-cell–mediated tumor regression. See related commentary by DelGiorno, p. 977

Published
2023
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17. Supplementary Table S1 from Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer

Author

Faraoni, Erika Y., primary, O'Brien, Baylee J., primary, Strickland, Lincoln N., primary, Osborn, Baron K., primary, Mota, Victoria, primary, Chaney, Jarod, primary, Atkins, Constance Lynn, primary, Cen, Putao, primary, Rowe, Julie, primary, Cardenas, Jessica, primary, Poulsen, Kyle L., primary, Wray, Curtis J., primary, Thosani, Nirav C., primary, and Bailey-Lundberg, Jennifer M., primary

Published
2023
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18. Supplementary Table S3 from CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer

Author

Faraoni, Erika Y., primary, Singh, Kanchan, primary, Chandra, Vidhi, primary, Le Roux, Olivereen, primary, Dai, Yulin, primary, Sahin, Ismet, primary, O'Brien, Baylee J., primary, Strickland, Lincoln N., primary, Li, Le, primary, Vucic, Emily, primary, Warner, Amanda N., primary, Pruski, Melissa, primary, Clark, Trent, primary, Van Buren, George, primary, Thosani, Nirav C., primary, Bynon, John S., primary, Wray, Curtis J., primary, Bar-Sagi, Dafna, primary, Poulsen, Kyle L., primary, Vornik, Lana A., primary, Savage, Michelle I., primary, Sei, Shizuko, primary, Mohammed, Altaf, primary, Zhao, Zhongming, primary, Brown, Powel H., primary, Mills, Tingting, primary, Eltzschig, Holger K., primary, McAllister, Florencia, primary, and Bailey-Lundberg, Jennifer M., primary

Published
2023
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19. Data from CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer

Author

Faraoni, Erika Y., primary, Singh, Kanchan, primary, Chandra, Vidhi, primary, Le Roux, Olivereen, primary, Dai, Yulin, primary, Sahin, Ismet, primary, O'Brien, Baylee J., primary, Strickland, Lincoln N., primary, Li, Le, primary, Vucic, Emily, primary, Warner, Amanda N., primary, Pruski, Melissa, primary, Clark, Trent, primary, Van Buren, George, primary, Thosani, Nirav C., primary, Bynon, John S., primary, Wray, Curtis J., primary, Bar-Sagi, Dafna, primary, Poulsen, Kyle L., primary, Vornik, Lana A., primary, Savage, Michelle I., primary, Sei, Shizuko, primary, Mohammed, Altaf, primary, Zhao, Zhongming, primary, Brown, Powel H., primary, Mills, Tingting, primary, Eltzschig, Holger K., primary, McAllister, Florencia, primary, and Bailey-Lundberg, Jennifer M., primary

Published
2023
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20. Abstract 5258: Preclinical testing of CD73 inhibitor AB680 for pancreatic cancer immunoprevention

Author

Strickland, Lincoln N., primary, Faraoni, Erika Y., additional, Mardik, Nicolette R., additional, Vornik, Lana, additional, Savage, Michelle I., additional, Sei, Shizuko, additional, Miller, Mark S., additional, Eltzschig, Holger K., additional, Brown, Powel H., additional, McAllister, Florencia, additional, and Bailey-Lundberg, Jennifer M., additional

Published
2023
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21. Supplementary Figures from CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer

Author

Faraoni, Erika Y., primary, Singh, Kanchan, primary, Chandra, Vidhi, primary, Le Roux, Olivereen, primary, Dai, Yulin, primary, Sahin, Ismet, primary, O'Brien, Baylee J., primary, Strickland, Lincoln N., primary, Li, Le, primary, Vucic, Emily, primary, Warner, Amanda N., primary, Pruski, Melissa, primary, Clark, Trent, primary, Van Buren, George, primary, Thosani, Nirav C., primary, Bynon, John S., primary, Wray, Curtis J., primary, Bar-Sagi, Dafna, primary, Poulsen, Kyle L., primary, Vornik, Lana A., primary, Savage, Michelle I., primary, Sei, Shizuko, primary, Mohammed, Altaf, primary, Zhao, Zhongming, primary, Brown, Powel H., primary, Mills, Tingting, primary, Eltzschig, Holger K., primary, McAllister, Florencia, primary, and Bailey-Lundberg, Jennifer M., primary

Published
2023
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22. Supplementary Data from Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer

Author

Faraoni, Erika Y., primary, O'Brien, Baylee J., primary, Strickland, Lincoln N., primary, Osborn, Baron K., primary, Mota, Victoria, primary, Chaney, Jarod, primary, Atkins, Constance Lynn, primary, Cen, Putao, primary, Rowe, Julie, primary, Cardenas, Jessica, primary, Poulsen, Kyle L., primary, Wray, Curtis J., primary, Thosani, Nirav C., primary, and Bailey-Lundberg, Jennifer M., primary

Published
2023
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23. Data from Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer

Author

Faraoni, Erika Y., primary, O'Brien, Baylee J., primary, Strickland, Lincoln N., primary, Osborn, Baron K., primary, Mota, Victoria, primary, Chaney, Jarod, primary, Atkins, Constance Lynn, primary, Cen, Putao, primary, Rowe, Julie, primary, Cardenas, Jessica, primary, Poulsen, Kyle L., primary, Wray, Curtis J., primary, Thosani, Nirav C., primary, and Bailey-Lundberg, Jennifer M., primary

Published
2023
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24. Supplementary Table S3 from CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer

Author

Jennifer M. Bailey-Lundberg, Florencia McAllister, Holger K. Eltzschig, Tingting Mills, Powel H. Brown, Zhongming Zhao, Altaf Mohammed, Shizuko Sei, Michelle I. Savage, Lana A. Vornik, Kyle L. Poulsen, Dafna Bar-Sagi, Curtis J. Wray, John S. Bynon, Nirav C. Thosani, George Van Buren, Trent Clark, Melissa Pruski, Amanda N. Warner, Emily Vucic, Le Li, Lincoln N. Strickland, Baylee J. O'Brien, Ismet Sahin, Yulin Dai, Olivereen Le Roux, Vidhi Chandra, Kanchan Singh, and Erika Y. Faraoni

Abstract

Table S3

Published
2023
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25. Supplementary Figures from CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer

Author

Jennifer M. Bailey-Lundberg, Florencia McAllister, Holger K. Eltzschig, Tingting Mills, Powel H. Brown, Zhongming Zhao, Altaf Mohammed, Shizuko Sei, Michelle I. Savage, Lana A. Vornik, Kyle L. Poulsen, Dafna Bar-Sagi, Curtis J. Wray, John S. Bynon, Nirav C. Thosani, George Van Buren, Trent Clark, Melissa Pruski, Amanda N. Warner, Emily Vucic, Le Li, Lincoln N. Strickland, Baylee J. O'Brien, Ismet Sahin, Yulin Dai, Olivereen Le Roux, Vidhi Chandra, Kanchan Singh, and Erika Y. Faraoni

Abstract

Supplementary Figures S1-9

Published
2023
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26. Supplementary Data from Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer

Author

Jennifer M. Bailey-Lundberg, Nirav C. Thosani, Curtis J. Wray, Kyle L. Poulsen, Jessica Cardenas, Julie Rowe, Putao Cen, Constance Lynn Atkins, Jarod Chaney, Victoria Mota, Baron K. Osborn, Lincoln N. Strickland, Baylee J. O'Brien, and Erika Y. Faraoni

Abstract

Supplementary Figures

Published
2023
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27. Supplementary Table S1 from Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer

Author

Jennifer M. Bailey-Lundberg, Nirav C. Thosani, Curtis J. Wray, Kyle L. Poulsen, Jessica Cardenas, Julie Rowe, Putao Cen, Constance Lynn Atkins, Jarod Chaney, Victoria Mota, Baron K. Osborn, Lincoln N. Strickland, Baylee J. O'Brien, and Erika Y. Faraoni

Abstract

Supplementary Table S1

Published
2023
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28. Data from Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer

Author

Jennifer M. Bailey-Lundberg, Nirav C. Thosani, Curtis J. Wray, Kyle L. Poulsen, Jessica Cardenas, Julie Rowe, Putao Cen, Constance Lynn Atkins, Jarod Chaney, Victoria Mota, Baron K. Osborn, Lincoln N. Strickland, Baylee J. O'Brien, and Erika Y. Faraoni

Abstract

Pancreatic ductal adenocarcinoma (PDAC) presents a 5-year overall survival rate of 11%, despite efforts to improve clinical outcomes in the past two decades. Therapeutic resistance is a hallmark of this disease, due to its dense and suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a promising local ablative and potential immunomodulatory therapy for PDAC. In this study, we performed RFA in a preclinical tumor-bearing KrasG12D; Trp53R172H/+; Pdx1:Cre (KPC) syngeneic model, analyzed local and abscopal affects after RFA and compared our findings with resected PDAC specimens. We found that RFA reduced PDAC tumor progression in vivo and promoted strong TME remodeling. In addition, we discovered tumor-infiltrating neutrophils determined abscopal effects. Using imaging mass cytometry, we showed that RFA elevated dendritic cell numbers in RFA-treated tumors and promoted a significant CD4+ and CD8+ T-cell abscopal response. In addition, RFA elevated levels of programmed death-ligand 1 (PD-L1) and checkpoint blockade inhibition targeting PD-L1 sustained tumor growth reduction in the context of RFA. This study indicates RFA treatment, which has been shown to increase tumor antigen shedding, promotes antitumor immunity. This is critical in PDAC where recent clinical immunotherapy trials have not resulted in substantial changes in overall survival.

Published
2023
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29. Data from CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer

Author

Jennifer M. Bailey-Lundberg, Florencia McAllister, Holger K. Eltzschig, Tingting Mills, Powel H. Brown, Zhongming Zhao, Altaf Mohammed, Shizuko Sei, Michelle I. Savage, Lana A. Vornik, Kyle L. Poulsen, Dafna Bar-Sagi, Curtis J. Wray, John S. Bynon, Nirav C. Thosani, George Van Buren, Trent Clark, Melissa Pruski, Amanda N. Warner, Emily Vucic, Le Li, Lincoln N. Strickland, Baylee J. O'Brien, Ismet Sahin, Yulin Dai, Olivereen Le Roux, Vidhi Chandra, Kanchan Singh, and Erika Y. Faraoni

Abstract

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin–dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by IHC and high-performance liquid chromatography. Analysis in human PDAC subtypes indicated that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC squamous and basal subtypes, considered to have the highest immunosuppression and worst prognosis. Multiplex immunofluorescent analysis showed that activated CD8+ T cells in the PDAC tumor microenvironment express high levels of CD73, indicating an opportunity for immunotherapeutic targeting. Delivery of CD73 small-molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. In addition, the adenosine receptor Adora2b was a determinant of adenosine-mediated immunosuppression in PDAC. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment elevated in the ductal cell of origin, linking biology with subtype classification, critical components for PDAC immunoprevention and personalized approaches for immunotherapeutic intervention.Significance:Ductal-derived pancreatic tumors have elevated epithelial and CD8+GZM+ T-cell CD73 expression that confers sensitivity to small-molecule inhibition of CD73 or Adora2b to promote CD8+ T-cell–mediated tumor regression.See related commentary by DelGiorno, p. 977

Published
2023
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30. Radiofrequency ablation remodels the tumor microenvironment and promotes neutrophil-mediated abscopal immunomodulation in pancreatic cancer

Author

Erika Y. Faraoni, Baylee J. O'Brien, Lincoln N. Strickland, Baron K. Osborn, Victoria Mota, Jarod Chaney, Constance Lynn Atkins, Putao Cen, Julie Rowe, Jessica Cardenas, Kyle L. Poulsen, Curtis J. Wray, Nirav C. Thosani, and Jennifer M. Bailey-Lundberg

Subjects
Cancer Research, Immunology, Article
Abstract

Pancreatic ductal adenocarcinoma (PDAC) presents a 5-year overall survival rate of 11%, despite efforts to improve clinical outcomes in the past two decades. Therapeutic resistance is a hallmark of this disease, due to its dense and suppressive tumor microenvironment (TME). Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising local ablative and potential immunomodulatory therapy for PDAC. In this study, we performed RFA in a preclinical tumor-bearing Kras(G12D); Trp53(R172H)/+; Pdx1:Cre (KPC) syngeneic model, analyzed local and abscopal affects after RFA and compared our findings with resected PDAC specimens. We found that RFA reduced PDAC tumor progression in vivo and promoted strong TME remodeling. Additionally, we discovered tumor-infiltrating neutrophils determined abscopal effects. Using imaging mass cytometry, we showed that RFA elevated dendritic cell numbers in RFA-treated tumors and promoted a significant CD4(+) and CD8(+) T-cell abscopal response. In addition, RFA elevated levels of PD-L1 and checkpoint blockade inhibition targeting PD-L1 sustained tumor growth reduction in the context of RFA. This study indicates RFA treatment, which has been shown to increase tumor antigen shedding, promotes antitumor immunity. This is critical in PDAC where recent clinical immunotherapy trials have not resulted in substantial changes in overall survival. SYNOPSIS: Novel immunotherapeutic strategies are needed to reduce PDAC mortality and metastatic potential. The data suggest that EUS-RFA provides an opportunity to address PDAC chemo- and immunotherapeutic resistance by stimulating the immune system and modulating the desmoplastic stroma.

Published
2023

31. <scp>CD73</scp> ‐generated extracellular adenosine promotes resolution of neutrophil‐mediated tissue injury and restrains metaplasia in pancreatitis

Author

Baylee J. O'Brien, Erika Y. Faraoni, Lincoln N. Strickland, Zhibo Ma, Victoria Mota, Samantha Mota, Xuebo Chen, Tingting Mills, Holger K. Eltzschig, Kathleen E. DelGiorno, and Jennifer M. Bailey‐Lundberg

Subjects
Inflammation, Metaplasia, Adenosine, Neutrophils, Biochemistry, Mice, Inbred C57BL, Mice, Pancreatitis, Chronic, Acute Disease, Genetics, Animals, 5'-Nucleotidase, Molecular Biology, Ceruletide, Biotechnology
Abstract

Pancreatitis is currently the leading cause of gastrointestinal hospitalizations in the US. This condition occurs in response to abdominal injury, gallstones, chronic alcohol consumption or, less frequently, the cause remains idiopathic. CD73 is a cell surface ecto-5'-nucleotidase that generates extracellular adenosine, which can contribute to resolution of inflammation by binding adenosine receptors on infiltrating immune cells. We hypothesized genetic deletion of CD73 would result in more severe pancreatitis due to decreased generation of extracellular adenosine. CD73 knockout (CD73

Published
2022
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32. CD73 ‐generated extracellular adenosine promotes resolution of neutrophil‐mediated tissue injury and restrains metaplasia in pancreatitis

Author

O'Brien, Baylee J., primary, Faraoni, Erika Y., additional, Strickland, Lincoln N., additional, Ma, Zhibo, additional, Mota, Victoria, additional, Mota, Samantha, additional, Chen, Xuebo, additional, Mills, Tingting, additional, Eltzschig, Holger K., additional, DelGiorno, Kathleen E., additional, and Bailey‐Lundberg, Jennifer M., additional

Published
2022
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33. Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer

Author

Faraoni, Erika Y., primary, O'Brien, Baylee J., additional, Strickland, Lincoln N., additional, Osborn, Baron K., additional, Mota, Victoria, additional, Chaney, Jarod, additional, Atkins, Constance Lynn, additional, Cen, Putao, additional, Rowe, Julie, additional, Cardenas, Jessica, additional, Poulsen, Kyle L., additional, Wray, Curtis J., additional, Thosani, Nirav C., additional, and Bailey-Lundberg, Jennifer M., additional

Published
2022
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35. CD73 generated extracellular adenosine promotes resolution of neutrophil-mediated tissue injury and restrains metaplasia in pancreatitis

Author

Baylee J. O’Brien, Erika Y. Faraoni, Lincoln N. Strickland, Zhibo Ma, Victoria Mota, Samantha Mota, Xuebo Chen, Tingting Mills, Holger K. Eltzschig, Kathleen E. DelGiorno, and Jennifer M. Bailey-Lundberg

Abstract

Background and AimsPancreatitis is currently the leading cause of gastrointestinal hospitalizations in the US. This condition occurs in response to abdominal injury, gallstones, chronic alcohol consumption or, less frequently, the cause remains idiopathic. CD73 is a cell surface ecto-5’-nucleotidase that generates extracellular adenosine, which can contribute to resolution of inflammation by binding adenosine receptors on infiltrating immune cells. We hypothesized genetic deletion of CD73 would result in more severe pancreatitis due to decreased generation of extracellular adenosine.MethodsCD73 knockout (CD73-/-) and C57BL/6 (wild type, WT) mice were used to evaluate the progression and response of caerulein-induced acute and chronic pancreatitis.ResultsIn response to caerulein-mediated chronic or acute pancreatitis, WT mice display resolution of pancreatitis at earlier timepoints than CD73-/- mice. Using immunohistochemistry and analysis of single cell RNA-seq (scRNA-seq) data, we determined CD73 localization in chronic pancreatitis is primarily observed in mucin/ductal cell populations and immune cells. In murine pancreata challenged with caerulein to induce acute pancreatitis, we compared CD73-/- to WT mice and observed a significant infiltration of Ly6G+, MPO+, and Granzyme B+ cells in CD73-/- compared to WT pancreata and we quantified a significant increase in acinar-to-ductal metaplasia demonstrating sustained metaplasia and inflammation in CD73-/- mice. Using neutrophil depletion in CD73-/- mice, we show neutrophil depletion significantly reduces metaplasia defined by CK19+ cells per field and significantly reduces acute pancreatitis.ConclusionsThese data identify CD73 agonists as a potential therapeutic strategy for patients with acute and chronic pancreatitis as adenosine generation and activation of adenosine receptors is critical to resolve persistent inflammation in the pancreas.Graphical Abstract

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2022
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36. CD73 generated extracellular adenosine promotes resolution of neutrophil-mediated tissue injury and restrains metaplasia in pancreatitis

Author

O’Brien, Baylee J., primary, Faraoni, Erika Y., additional, Strickland, Lincoln N., additional, Ma, Zhibo, additional, Mota, Victoria, additional, Mota, Samantha, additional, Chen, Xuebo, additional, Mills, Tingting, additional, Eltzschig, Holger K., additional, DelGiorno, Kathleen E., additional, and Bailey-Lundberg, Jennifer M., additional

Published
2022
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38. Abstract 5258: Preclinical testing of CD73 inhibitor AB680 for pancreatic cancer immunoprevention

Author

Lincoln N. Strickland, Erika Y. Faraoni, Nicolette R. Mardik, Lana Vornik, Michelle I. Savage, Shizuko Sei, Mark S. Miller, Holger K. Eltzschig, Powel H. Brown, Florencia McAllister, and Jennifer M. Bailey-Lundberg

Subjects
Cancer Research, Oncology
Abstract

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a profoundly immunosuppressive microenvironment. Innovative therapeutic strategies are urgently needed to stop the progression of precancerous lesions into aggressive PDAC, which remains a lethal malignancy. The goal of this research project is to test immunopreventive strategies by targeting the 5’ ectonucleotidase enzyme, CD73, one of the gatekeeper enzymes responsible for conversion of adenosine monophosphate (AMP), to an immunosuppressive metabolite, adenosine, in the tumor microenvironment (TME). We hypothesize that inhibition of CD73 will prevent pancreatic intraepithelial neoplasia (PanIN) formation and progression to PDAC by reversing adenosine directed immunosuppression. This research explores immunopreventive strategies aimed to restore tumor immune surveillance to prevent cancer initiation or progression. Materials and methods: We used two models: a syngeneic model of PDAC using cells derived from KrasG12D;Trp53R172H/+;PdxCre (KPC) mice and a KrasG12D;PdxCre (KC) genetically engineered mouse model (GEM) of PDAC. Oral gavage of AB680 (small molecule CD73 inhibitor) was given three days/week at 10mg/kg starting the day after KPC injections and tumor sizes were measured weekly. In the GEM model, the same treatment regimen began when the mice were between 6 and 9 weeks old and were euthanized either between 15 and 20 weeks of age or around 27 weeks of age, and pancreas tissue was harvested. Histology was analyzed and 6 fields per mouse were quantified using ImageJ. Results: As we have described (Singh, et al, bioRxiv), in the syngeneic model, there was a significant reduction in tumor growth and significant increase in activated CD8-positive T cells, dendritic cells, and macrophages from AB680 treated mice. The intratumoral adenosine levels were significantly decreased in AB680 treated mice compared to vehicle treated mice. In the KC GEM model, we quantified significantly fewer early PanIN lesions (p=0.0328), a trend in decreased advanced PanIN (p=0.0641), and significant decrease in PDAC (p=0.0058) in the AB680 treated mice when compared to the vehicle treated mice. We quantified abundance of collagen deposition as a marker of fibrosis and observed significantly decreased collagen (p Conclusion: Inhibiting CD73 restructures TME and reduces PanIN incidence and progression to PDAC. CD73 inhibition may be a candidate immunoprevention strategy in pancreatic cancer. [Supported by NCI 75N91019D00021/75N91020F00002] Citation Format: Lincoln N. Strickland, Erika Y. Faraoni, Nicolette R. Mardik, Lana Vornik, Michelle I. Savage, Shizuko Sei, Mark S. Miller, Holger K. Eltzschig, Powel H. Brown, Florencia McAllister, Jennifer M. Bailey-Lundberg. Preclinical testing of CD73 inhibitor AB680 for pancreatic cancer immunoprevention. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5258.

Published
2023
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39. Patient Education in Thyrotoxicosis.

Author

Lincoln, N. B., Sturrock, N. D. C., Sowter, H., Abbott-Harland, S., Nichols, E., and Jeffcoate, W. J.

Abstract

Study aims to assess the need for a thyrotoxicosis patient education programs and evaluates a group education session. Patients with thyrotoxicosis were surveyed to assess their needs. Determined that people with thyrotoxicosis had limited knowledge about their condition. The offer of a group education program has little effect on that knowledge but was associated with a reduction in anxiety. (Author/JDM)

Published
2000

40. Radiofrequency ablation remodels the tumor microenvironment and promotes systemic immunomodulation in pancreatic cancer

Author

Erika Y. Faraoni, Nirav C. Thosani, Baylee O’Brien, Lincoln N. Strickland, Victoria Mota, Jarod Chaney, Putao Cen, Julie Rowe, Jessica Cardenas, Kyle L. Poulsen, Curtis J. Wray, and Jennifer Bailey-Lundberg

Subjects
surgical procedures, operative
Abstract

Background and AimsPancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to therapy. A major contributing factor to therapeutic failure is profound desmoplasia and a well-documented hypoxic tumor microenvironment (TME). In PDAC, several therapeutic approaches, including chemotherapy and radiation alone or combined with immune checkpoint inhibitors, have shown minimal therapeutic success, placing an imperative need for the discovery and application of innovative treatments. Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising immunomodulator therapy for PDAC. In this work, we hypothesized RFA promotes local and systemic stromal and immunomodulating effects that can be identified for new combination therapeutic strategies.MethodsTo test our hypothesis, a syngeneic PDAC mouse model was performed by symmetrically injecting 100k murine KPC cells in bilateral flanks of C57BL/6 female mice. RFA treatment initiated when tumors reached 200-500 mm3 and was performed only in the right flank. The left flank tumor (non-RFA contralateral side) was used as a paired control for further analysis.ResultsRFA promoted a significant reduction in tumor growth rate 4 days after treatment in RFA treated and non-RFA side contralateral tumors from treated mice when compared to controls. Histological analysis revealed a significant increase in expression of cleaved Caspase3 in RFA treated tumors. In addition, collagen deposition and CD31+ cells were significantly elevated in RFA side and non-RFA contralateral tumors from RFA treated mice. Proteome profiling showed changes in C5a and IL-23 in RFA responsive tumors, indicating a role of RFA in modulating intratumoral inflammatory responses.ConclusionsThese data indicate RFA promotes local and systemic anti-tumor responses in a syngeneic mouse model of PDAC implicating RFA treatment for local tumors as well as metastatic disease.Graphical Abstract

Published
2022
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41. A Crossover Trial Evaluating an Educational-Behavioral Joint Protection Programme for People with Rheumatoid Arthritis.

Author

Hammond, A., Lincoln, N., and Sutcliffe, L.

Abstract

Joint protection, a self-management technique taught to people with rheumatoid arthritis, was used in a group education program. A crossover trial (N=35) was conducted. No significant changes in measures of pain, functional disability, grip strength, self-efficacy or helplessness occurred post-education, although this may have been due to the small sample size. (Author/MKA)

Published
1999

42. The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer.

Author

Strickland, Lincoln N., Faraoni, Erika Y., Wei Ruan, Xiaoyi Yuan, Eltzschig, Holger K., and Bailey-Lundberg, Jennifer M.

Subjects
CYTOTOXIC T cells, KILLER cells, PANCREATIC cancer, PANCREATIC intraepithelial neoplasia, B cells, T cells
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma that impedes drug delivery, reduces parenchymal blood flow, and suppresses the anti-tumor immune response. The extracellular matrix and abundance of stromal cells result in severe hypoxia within the tumor microenvironment (TME), and emerging publications evaluating PDAC tumorigenesis have shown the adenosine signaling pathway promotes an immunosuppressive TME and contributes to the overall low survival rate. Hypoxia increases many elements of the adenosine signaling pathway, resulting in higher adenosine levels in the TME, further contributing to immune suppression. Extracellular adenosine signals through 4 adenosine receptors (Adora1, Adora2a, Adora2b, Adora3). Of the 4 receptors, Adora2b has the lowest affinity for adenosine and thus, has important consequences when stimulated by adenosine binding in the hypoxic TME. We and others have shown that Adora2b is present in normal pancreas tissue, and in injured or diseased pancreatic tissue, Adora2b levels are significantly elevated. The Adora2b receptor is present on many immune cells, including macrophages, dendritic cells, natural killer cells, natural killer T cells, γκ T cells, B cells, T cells, CD4+ T cells, and CD8+ T cells. In these immune cell types, adenosine signaling through Adora2b can reduce the adaptive anti-tumor response, augmenting immune suppression, or may contribute to transformation and changes in fibrosis, perineural invasion, or the vasculature by binding the Adora2b receptor on neoplastic epithelial cells, cancer-associated fibroblasts, blood vessels, lymphatic vessels, and nerves. In this review, we discuss the mechanistic consequences of Adora2b activation on cell types in the tumor microenvironment. As the cell-autonomous role of adenosine signaling through Adora2b has not been comprehensively studied in pancreatic cancer cells, we will also discuss published data from other malignancies to infer emerging therapeutic considerations for targeting the Adora2b adenosine receptor to reduce the proliferative, invasive, and metastatic potential of PDAC cells. [ABSTRACT FROM AUTHOR]

Published
2023
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43. Radiofrequency ablation remodels the tumor microenvironment and promotes systemic immunomodulation in pancreatic cancer

Author

Faraoni, Erika Y., primary, Thosani, Nirav C., additional, O’Brien, Baylee, additional, Strickland, Lincoln N., additional, Mota, Victoria, additional, Chaney, Jarod, additional, Cen, Putao, additional, Rowe, Julie, additional, Cardenas, Jessica, additional, Poulsen, Kyle L., additional, Wray, Curtis J., additional, and Bailey-Lundberg, Jennifer, additional

Published
2022
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