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2. Harnessing Artificial Intelligence to Infer Novel Spatial Biomarkers for the Diagnosis of Eosinophilic Esophagitis

Author

Larey, Ariel, Aknin, Eliel, Daniel, Nati, Osswald, Garrett A., Caldwell, Julie M., Rochman, Mark, Wasserman, Tanya, Collins, Margaret H., Arva, Nicoleta C., Yang, Guang-Yu, Rothenberg, Marc E., and Savir, Yonatan

Subjects
Computer Science - Artificial Intelligence, Computer Science - Computer Vision and Pattern Recognition, Quantitative Biology - Quantitative Methods
Abstract

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory condition of the esophagus associated with elevated esophageal eosinophils. Second only to gastroesophageal reflux disease, EoE is one of the leading causes of chronic refractory dysphagia in adults and children. EoE diagnosis requires enumerating the density of esophageal eosinophils in esophageal biopsies, a somewhat subjective task that is time-consuming, thus reducing the ability to process the complex tissue structure. Previous artificial intelligence (AI) approaches that aimed to improve histology-based diagnosis focused on recapitulating identification and quantification of the area of maximal eosinophil density. However, this metric does not account for the distribution of eosinophils or other histological features, over the whole slide image. Here, we developed an artificial intelligence platform that infers local and spatial biomarkers based on semantic segmentation of intact eosinophils and basal zone distributions. Besides the maximal density of eosinophils (referred to as Peak Eosinophil Count [PEC]) and a maximal basal zone fraction, we identify two additional metrics that reflect the distribution of eosinophils and basal zone fractions. This approach enables a decision support system that predicts EoE activity and classifies the histological severity of EoE patients. We utilized a cohort that includes 1066 biopsy slides from 400 subjects to validate the system's performance and achieved a histological severity classification accuracy of 86.70%, sensitivity of 84.50%, and specificity of 90.09%. Our approach highlights the importance of systematically analyzing the distribution of biopsy features over the entire slide and paves the way towards a personalized decision support system that will assist not only in counting cells but can also potentially improve diagnosis and provide treatment prediction., Comment: AL, EA, and ND have contributed equally to this work and share first authorship. YS is the corresponding author, e-mail: yoni.savir@technion.ac.il

Published
2022

3. Losartan Treatment Reduces Esophageal Eosinophilic Inflammation in a Subset of Eosinophilic Esophagitis

Author

Wechsler, Joshua, Davis, Carla, Furuta, Glenn, Khoury, Paneez, Gupta, Sandeep K., Spergel, Jonathan, Leung, John, Menard-Katcher, Paul, Falk, Gary, Gonsalves, Nirmala Prabu, Peterson, Kathryn, Abonia, J. Pablo, Rudman Spergel, Amanda K., Hirano, Ikuo, Shoda, Tetsuo, Zhang, Xue, Martin, Lisa J., Mukkada, Vincent A., Putnam, Philip E., Blacklidge, Melodie, Neilson, Derek, Collins, Margaret H., Yang, Guang-Yu, Capocelli, Kelley E., Foote, Heather, Eby, Mike, Dong, Stephanie, Aceves, Seema S., and Rothenberg, Marc E.

Published
2024
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5. Clinical and molecular correlates of the Index of Severity for Eosinophilic Esophagitis

Author

Sato, Hiroki, Dellon, Evan S., Aceves, Seema S., Arva, Nicoleta C., Chehade, Mirna, Collins, Margaret H., Davis, Carla M., Falk, Gary W., Furuta, Glenn T., Gonsalves, Nirmala P., Gupta, Sandeep K., Hirano, Ikuo, Hiremath, Girish, Katzka, David A., Khoury, Paneez, Leung, John, Menard-Katcher, Paul, Pesek, Robbie, Peterson, Kathryn A., Pletneva, Maria A., Spergel, Jonathan M., Wechsler, Joshua B., Yang, Guang-Yu, Rothenberg, Marc E., and Shoda, Tetsuo

Published
2024
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9. Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer

Author

Bui, Triet M., Yalom, Lenore K., Ning, Edward, Urbanczyk, Jessica M., Ren, Xingsheng, Herrnreiter, Caroline J., Disario, Jackson A., Wray, Brian, Schipma, Matthew J., Velichko, Yuri S., Sullivan, David P., Abe, Kouki, Lauberth, Shannon M., Yang, Guang-Yu, Dulai, Parambir S., Hanauer, Stephen B., and Sumagin, Ronen

Subjects
Tumors -- Development and progression, Ulcerative colitis -- Development and progression, Colorectal cancer -- Development and progression, Health care industry
Abstract

Neutrophil (PMN) tissue accumulation is an established feature of ulcerative colitis (UC) lesions and colorectal cancer (CRC). To assess the PMN phenotypic and functional diversification during the transition from inflammatory ulceration to CRC we analyzed the transcriptomic landscape of blood and tissue PMNs. Transcriptional programs effectively separated PMNs based on their proximity to peripheral blood, inflamed colon, and tumors. In silico pathway overrepresentation analysis, proteinnetwork mapping, gene signature identification, and gene-ontology scoring revealed unique enrichment of angiogenic and vasculature development pathways in tumor-associated neutrophils (TANs). Functional studies utilizing ex vivo cultures, colitis-induced murine CRC, and patient-derived xenograft models demonstrated a critical role for TANs in promoting tumor vascularization. Spp1 (OPN) and Mmp14 (MT1-MMP) were identified by unbiased -omics and mechanistic studies to be highly induced in TANs, acting to critically regulate endothelial cell chemotaxis and branching. TCGA data set and clinical specimens confirmed enrichment of SPP1 and MMP14 in high-grade CRC but not in patients with UC. Pharmacological inhibition of TAN trafficking or MMP14 activity effectively reduced tumor vascular density, leading to CRC regression. Our findings demonstrate a niche-directed PMN functional specialization and identify TAN contributions to tumor vascularization, delineating what we believe to be a new therapeutic framework for CRC treatment focused on TAN angiogenic properties., Introduction Neutrophils (PMNs) robustly localize to active ulcerative colitis (UC) lesions and the colorectal cancer (CRC) microenvironment. Colitis-associated CRC, in particular, features en masse intratumoral PMN accumulation (1-6). However, across [...]

Published
2024
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11. PECNet: A Deep Multi-Label Segmentation Network for Eosinophilic Esophagitis Biopsy Diagnostics

Author

Daniel, Nati, Larey, Ariel, Aknin, Eliel, Osswald, Garrett A., Caldwell, Julie M., Rochman, Mark, Collins, Margaret H., Yang, Guang-Yu, Arva, Nicoleta C., Capocelli, Kelley E., Rothenberg, Marc E., and Savir, Yonatan

Subjects
Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning, Electrical Engineering and Systems Science - Image and Video Processing, Quantitative Biology - Quantitative Methods
Abstract

Background. Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus associated with elevated numbers of eosinophils. Disease diagnosis and monitoring requires determining the concentration of eosinophils in esophageal biopsies, a time-consuming, tedious and somewhat subjective task currently performed by pathologists. Methods. Herein, we aimed to use machine learning to identify, quantitate and diagnose EoE. We labeled more than 100M pixels of 4345 images obtained by scanning whole slides of H&E-stained sections of esophageal biopsies derived from 23 EoE patients. We used this dataset to train a multi-label segmentation deep network. To validate the network, we examined a replication cohort of 1089 whole slide images from 419 patients derived from multiple institutions. Findings. PECNet segmented both intact and not-intact eosinophils with a mean intersection over union (mIoU) of 0.93. This segmentation was able to quantitate intact eosinophils with a mean absolute error of 0.611 eosinophils and classify EoE disease activity with an accuracy of 98.5%. Using whole slide images from the validation cohort, PECNet achieved an accuracy of 94.8%, sensitivity of 94.3%, and specificity of 95.14% in reporting EoE disease activity. Interpretation. We have developed a deep learning multi-label semantic segmentation network that successfully addresses two of the main challenges in EoE diagnostics and digital pathology, the need to detect several types of small features simultaneously and the ability to analyze whole slides efficiently. Our results pave the way for an automated diagnosis of EoE and can be utilized for other conditions with similar challenges.

Published
2021

12. Design and Application of Auxiliary Bid Evaluation System Based on Big Data and Image Recognition Technology

Author

Wu, Zhi-wei, He, Ping, Dong, Bing, Yang, Guang-yu, Zhang, Yi-fei, Dou, Runliang, Editor-in-Chief, Liu, Jing, Editor-in-Chief, Khasawneh, Mohammad T., Editor-in-Chief, Balas, Valentina Emilia, Series Editor, Bhowmik, Debashish, Series Editor, Khan, Khalil, Series Editor, Masehian, Ellips, Series Editor, Mohammadi-Ivatloo, Behnam, Series Editor, Nayyar, Anand, Series Editor, Pamucar, Dragan, Series Editor, Shu, Dewu, Series Editor, Akhtar, Nadeem, editor, Draman, Azah Kamilah, editor, and Abdollah, Mohd Faizal, editor

Published
2023
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13. One-food versus 4-food elimination diet for pediatric eosinophilic esophagitis: A multisite randomized trial

Author

Kliewer, Kara L., Abonia, J. Pablo, Aceves, Seema S., Atkins, Dan, Bonis, Peter A., Capocelli, Kelley E., Chehade, Mirna, Collins, Margaret H., Dellon, Evan S., Fei, Lin, Furuta, Glenn T., Gupta, Sandeep K., Kagalwalla, Amir, Leung, John, Mir, Sabina, Mukkada, Vincent A., Pesek, Robbie, Rosenberg, Chen, Shoda, Tetsuo, Spergel, Jonathan M., Sun, Qin, Wechsler, Joshua B., Yang, Guang-Yu, and Rothenberg, Marc E.

Published
2024
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14. Long-term durability between parent and child patient-reported outcomes in eosinophilic esophagitis

Author

Martin, Lisa J., Zhang, Xue, Chehade, Mirna, Davis, Carla M., Dellon, Evan S., Falk, Gary W., Gupta, Sandeep K., Hirano, Ikuo, Hiremath, Girish S., Katzka, David A., Khoury, Paneez, Leung, John, Menard-Katcher, Paul, Gonsalves, Nirmala, Pesek, Robert D., Spergel, Jonathan M., Wechsler, Joshua B., Kliewer, Kara, Arva, Nicoleta C., Collins, Margaret H., Pletneva, Maria, Yang, Guang-Yu, Furuta, Glenn T., Rothenberg, Marc E., and Aceves, Seema S.

Published
2024
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15. Nonepithelial Gene Expression Correlates With Symptom Severity in Adults With Eosinophilic Esophagitis

Author

Kim, Seung, Ben-Baruch Morgenstern, Netali, Osonoi, Kasumi, Aceves, Seema S., Arva, Nicoleta C., Chehade, Mirna, Collins, Margaret H., Dellon, Evan S., Falk, Gary W., Furuta, Glenn T., Gonsalves, Nirmala P., Gupta, Sandeep K., Hirano, Ikuo, Hiremath, Girish, Katzka, David A., Khoury, Paneez, Leung, John, Pesek, Robbie, Peterson, Kathryn A., Pletneva, Maria A., Spergel, Jonathan M., Wechsler, Joshua B., Yang, Guang-Yu, Rothenberg, Marc E., and Shoda, Tetsuo

Published
2024
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18. Esophageal Epithelium and Lamina Propria Are Unevenly Involved in Eosinophilic Esophagitis

Author

Hiremath, Girish, Sun, Lili, Collins, Margaret H., Bonis, Peter A., Arva, Nicoleta C., Capocelli, Kelley E., Chehade, Mirna, Davis, Carla M., Falk, Gary W., Gonsalves, Nirmala, Gupta, Sandeep K., Hirano, Ikuo, Leung, John, Khoury, Paneez, Mukkada, Vincent A., Martin, Lisa J., Spergel, Jonathan M., Wechsler, Joshua B., Yang, Guang-Yu, Aceves, Seema S., Furuta, Glenn T., Rothenberg, Marc.E., Koyama, Tatsuki, and Dellon, Evan S.

Published
2023
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24. One-food versus six-food elimination diet therapy for the treatment of eosinophilic oesophagitis: a multicentre, randomised, open-label trial

Author

Kliewer, Kara L, Gonsalves, Nirmala, Dellon, Evan S, Katzka, David A, Abonia, Juan P, Aceves, Seema S, Arva, Nicoleta C, Besse, John A, Bonis, Peter A, Caldwell, Julie M, Capocelli, Kelley E, Chehade, Mirna, Cianferoni, Antonella, Collins, Margaret H, Falk, Gary W, Gupta, Sandeep K, Hirano, Ikuo, Krischer, Jeffrey P, Leung, John, Martin, Lisa J, Menard-Katcher, Paul, Mukkada, Vincent A, Peterson, Kathryn A, Shoda, Tetsuo, Rudman Spergel, Amanda K, Spergel, Jonathan M, Yang, Guang-Yu, Zhang, Xue, Furuta, Glenn T, and Rothenberg, Marc E

Published
2023
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25. Molecular, endoscopic, histologic, and circulating biomarker-based diagnosis of eosinophilic gastritis: Multi-site study

Author

Shoda, Tetsuo, Wen, Ting, Caldwell, Julie M, Collins, Margaret H, Besse, John A, Osswald, Garrett A, Abonia, J Pablo, Arva, Nicoleta C, Atkins, Dan, Capocelli, Kelley E, Dellon, Evan S, Falk, Gary W, Gonsalves, Nirmala, Gupta, Sandeep K, Hirano, Ikuo, Mukkada, Vincent A, Putnam, Philip E, Sheridan, Rachel M, Spergel, Amanda K Rudman, Spergel, Jonathan M, Wechsler, Joshua B, Yang, Guang-Yu, Aceves, Seema S, Furuta, Glenn T, Rothenberg, Marc E, and Researchers, Consortium of Eosinophilic Gastrointestinal Disease

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Digestive Diseases, Clinical Research, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Adolescent, Adult, Biomarkers, Child, Cytokines, Endoscopy, Gastrointestinal, Enteritis, Eosinophilia, Female, Gastritis, Humans, Male, Biomarker, diagnostic panel, eosinophil, eosinophilic gastritis, transcriptome, Consortium of Eosinophilic Gastrointestinal Disease Researchers, Immunology, Allergy
Abstract

BackgroundEosinophilic gastritis (EG) is a clinicopathologic disorder with marked gastric eosinophilia and clinical symptoms. There is an unmet need among patients with EG for more precise diagnostic tools.ObjectiveWe aimed to develop tissue- and blood-based diagnostic platforms for EG.MethodsPatients with EG and control subjects without EG were enrolled across 9 Consortium of Eosinophilic Gastrointestinal Disease Researchers-associated sites. An EG Diagnostic Panel (EGDP; gastric transcript subset) and EG blood biomarker panel (protein multiplex array) were analyzed. EGDP18 scores were derived from the expression of 18 highly dysregulated genes, and blood EG scores were derived from dysregulated cytokine/chemokine levels.ResultsGastric biopsy specimens and blood samples from 185 subjects (patients with EG, n = 74; control subjects without EG, n = 111) were analyzed. The EGDP (1) identified patients with active EG (P < .0001, area under the curve ≥ 0.95), (2) effectively monitored disease activity in longitudinal samples (P = .0078), (3) highly correlated in same-patient samples (antrum vs body, r = 0.85, P < .0001), and (4) inversely correlated with gastric peak eosinophil levels (r = -0.83, P < .0001), periglandular circumferential collars (r = -0.73, P < .0001), and endoscopic nodularity (r = -0.45, P < .0001). For blood-based platforms, eotaxin-3, thymus and activation-regulated chemokine, IL-5, and thymic stromal lymphopoietin levels were significantly increased. Blood EG scores (1) distinguished patients with EG from control subjects without EG (P < .0001, area under the curve ≥ 0.91), (2) correlated with gastric eosinophil levels (plasma: r = 0.72, P = .0002; serum: r = 0.54, P = .0015), and (3) inversely correlated with EGDP18 scores (plasma: r = -0.64, P = .0015; serum: r = -0.46, P = .0084). Plasma eotaxin-3 levels strongly associated with gastric CCL26 expression (r = 0.81, P < .0001).ConclusionWe developed tissue- and blood-based platforms for assessment of EG and uncovered robust associations between specific gastric molecular profiles and histologic and endoscopic features, providing insight and clinical readiness tools for this emerging rare disease.

Published
2020

29. List of contributors

Author

Agarwal, Anshika, primary, Albogami, Sarah, additional, Bairagi, Nandadulal, additional, Balasubramanian, Krishnan, additional, Basak, Subhash C., additional, Benfenati, Emilio, additional, Bhattacharjee, Apurba K., additional, Bhrdwaj, Anushka, additional, Chakravarti, Suman K., additional, Chattaraj, Pratim Kumar, additional, Chatterjee, Samrat, additional, Davuluri, Ramana V., additional, Dey, Tathagata, additional, Ghosh, Abhik, additional, Ghosh, Indira, additional, Gini, Giuseppina, additional, Hazarika, Lima, additional, Hu, Guang, additional, Hung, Chiakang, additional, Hussain, Tajamul, additional, Ji, Yanrong, additional, Joshi, Isha, additional, Khan, Taushif, additional, Khandelwal, Ravina, additional, Kumar, Pawan, additional, Kumar, Shivam, additional, Li, Min, additional, Liao, Jie, additional, Lungu, Claudiu N., additional, Majumdar, Subhabrata, additional, Mishra, Rama K., additional, Mohan, Manju, additional, Nandy, Ashesh, additional, Nayarisseri, Anuraj, additional, Nilar, Shahul H., additional, Pal, Ranita, additional, Pande, Aditi, additional, Restrepo, Guillermo, additional, Sarmah, Dipanka Tanu, additional, Sen, Dwaipayan, additional, Singh, Sanjeev Kumar, additional, Srija, Chillamcherla Dhanalakshmi, additional, Suresh, Revathy Arya, additional, Tang, Muyun, additional, Thakur, Garima, additional, Tong, Xin, additional, Vracko, Marjan, additional, Vračko, Marjan, additional, Wang, Ze, additional, Xu, DanDan, additional, and Yang, Guang-Yu, additional

Published
2023
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39. International Consensus Recommendations for Eosinophilic Gastrointestinal Disease Nomenclature

Author

Dellon, Evan S., Gonsalves, Nirmala, Abonia, J. Pablo, Alexander, Jeffrey A., Arva, Nicoleta C., Atkins, Dan, Attwood, Stephen E., Auth, Marcus K.H., Bailey, Dominique D., Biederman, Luc, Blanchard, Carine, Bonis, Peter A., Bose, Paroma, Bredenoord, Albert J., Chang, Joy W., Chehade, Mirna, Collins, Margaret H., Di Lorenzo, Carlo, Dias, Jorge Amil, Dohil, Ranjan, Dupont, Christophe, Falk, Gary W., Ferreira, Cristina T., Fox, Adam T., Genta, Robert M., Greuter, Thomas, Gupta, Sandeep K., Hirano, Ikuo, Hiremath, Girish S., Horsley-Silva, Jennifer L., Ishihara, Shunji, Ishimura, Norihisa, Jensen, Elizabeth T., Gutiérrez-Junquera, Carolina, Katzka, David A., Khoury, Paneez, Kinoshita, Yoshikazu, Kliewer, Kara L., Koletzko, Sibylle, Leung, John, Liacouras, Chris A., Lucendo, Alfredo J., Martin, Lisa J., McGowan, Emily C., Menard-Katcher, Calies, Metz, David C., Miller, Talya L., Moawad, Fouad J., Muir, Amanda B., Mukkada, Vincent A., Murch, Simon, Nhu, Quan M., Nomura, Ichiro, Nurko, Samuel, Ohtsuka, Yoshikazu, Oliva, Salvatore, Orel, Rok, Papadopoulou, Alexandra, Patel, Dhyanesh A., Pesek, Robert D., Peterson, Kathryn A., Philpott, Hamish, Putnam, Philip E., Richter, Joel E., Rosen, Rachel, Ruffner, Melanie A., Safroneeva, Ekaterina, Schreiner, Philipp, Schoepfer, Alain, Schroeder, Shauna R., Shah, Neil, Souza, Rhonda F., Spechler, Stuart J., Spergel, Jonathan M., Straumann, Alex, Talley, Nicholas J., Thapar, Nikhil, Vandenplas, Yvan, Venkatesh, Rajitha D., Vieira, Mario C., von Arnim, Ulrike, Walker, Marjorie M., Wechsler, Joshua B., Wershil, Barry K., Wright, Benjamin L., Yamada, Yoshiyuki, Yang, Guang-Yu, Zevit, Noam, Rothenberg, Marc E., Furuta, Glenn T., and Aceves, Seema S.

Published
2022
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40. Inhibition of Pancreatic Carcinoma Growth Through Enhancing ω-3 Epoxy Polyunsaturated Fatty Acid Profile by Inhibition of Soluble Epoxide Hydrolase.

Author

Xia, Rong, Sun, Leyu, Liao, Jie, Li, Haonan, You, Xiaoming, Xu, Dandan, Yang, Jun, Hwang, Sung Hee, Jones, Ryan D, Hammock, Bruce, and Yang, Guang-Yu

Subjects
Cell Line, Tumor, Animals, Mice, Inbred C57BL, Mice, Transgenic, Adenocarcinoma, Pancreatic Neoplasms, Epoxy Compounds, Fatty Acid Desaturases, Fatty Acids, Omega-3, Caenorhabditis elegans Proteins, Cell Proliferation, Dietary Supplements, Polyunsaturated fatty acid, epoxy fatty acid, fat-1, pancreatic cancer, soluble epoxide hydrolase, Pancreatic Cancer, Nutrition, Cancer, Digestive Diseases, Rare Diseases, Prevention of disease and conditions, and promotion of well-being, 3.3 Nutrition and chemoprevention, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BACKGROUND/AIM:Cytochrome P450 epoxygenase is a major enzyme involved in the metabolism of ω-3 polyunsaturated fatty acids (PUFAs) to produce biologically active ω-3 epoxy fatty acids (ω-3 epoxides). In general, all epoxy PUFAs including ω-3 epoxides are quickly metabolized/inactivated by soluble epoxide hydrolase (sEH) to form diol products. The aims of this study were to determine the effect and mechanism of fat-1 transgene, and ω-3 PUFA combined with sEH gene knockout or inhibitor on inhibiting pancreatic cancer and the related mechanisms involved. MATERIALS AND METHODS:PK03-mutant KrasG12D murine pancreatic carcinoma cells were inoculated into mouse models including fat-1, sEH-/- and C57BL/6J mice. The mice were fed with AIN-76A diet with or without ω-3 PUFA supplementation or treated with sEH inhibitor. In addition to tumor growth (tumor size and weight), cell proliferation, mutant Kras-mediated signaling, inflammatory reaction and angiogenesis were analyzed immunohisto-chemically and by western blot assay. ω-3 PUFA metabolism, particularly focusing on ω-3 epoxy fatty acids (ω-3 epoxides), was measured using a liquid chromatography with tandem mass spectrometry (LC-MS/MS) approach. RESULTS:Significant decreases of weight and size of the PK03 pancreatic carcinoma were observed in the fat-1 transgenic mice treated with sEH inhibitor compared to those of C57BL/6J control mice fed with AIN-76A diet (weight: 0.28±0.04 g vs. 0.58±0.06 g; size: 187.0±17.5 mm3 vs. 519.3±60.6 mm3). In a separate experiment, sEH-/- mice fed ω-3 PUFA supplement and C57BL/6J mice treated with sEH inhibitor and fed ω-3 PUFA supplement exhibited a significant reduction in the weight and size of the pancreatic carcinoma compared to C57BL/6J control mice (weight: 0.26±.26 g and 0.39±.39 g vs. 0.69±0.11 g, respectively; size: 274.2±36.2 mm3 and 296.4±99.8 mm3 vs. 612.6±117.8 mm3, respectively). Moreover, compared to the pancreatic tumors in C57BL/6J control mice, the tumors in fat-1 transgenic mice treated with sEH inhibitor showed a significant less inflammatory cell infiltrate (62.6±9.2/HPF (high power field) vs. 8.0±1.2/HPF), tumor cell proliferation (48.5±1.7% vs. 16.5±1.6%), and angiogenesis (micro-vessel density (MVD): 35.0±1.0 vs. 11.1±0.5) immunohistochemically, as well as significantly increased caspase-3 labeled apoptosis (0.44±0.06% vs. 0.69±0.06%, respectively). Using western blot approach, significant inhibition of mutant Kras-activated signals including phosphorylated Serine/threonine kinases (cRAF), Mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK) were identified in pancreatic carcinoma of fat-1 transgenic mice treated with sEH inhibitor. Eicosanoic acid metabolic profiling of the serum specimens detected a significant increase of the ratios of epoxides to dihydroxy fatty acid (DiHDPE) for docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and epoxides/dihydroxy octadecenoic acid (DiHOME) for arachidonic acid (ARA) and linoleic acid (LA), as well as a significant increase of epoxy metabolites of DHA, EPA, ARA and LA in fat-1 transgenic mice treated with a sEH inhibitor. CONCLUSION:ω-3 epoxy products from ω-3 PUFA metabolism play a crucial role in inhibiting pancreatic cancer growth, and use of ω-3 PUFAs combined with sEH inhibition is a strategy with high potential for pancreatic cancer treatment and prevention.

Published
2019

41. Variation in Endoscopic Activity Assessment and Endoscopy Score Validation in Adults With Eosinophilic Esophagitis

Author

Schoepfer, Alain M, Hirano, Ikuo, Coslovsky, Michael, Roumet, Marie C, Zwahlen, Marcel, Kuehni, Claudia E, Hafner, David, Alexander, Jeffrey A, Dellon, Evan S, Gonsalves, Nirmala, Leung, John, Bussmann, Christian, Collins, Margaret H, Newbury, Robert O, Smyrk, Thomas C, Woosley, John T, Yang, Guang-Yu, Romero, Yvonne, Katzka, David A, Furuta, Glenn T, Gupta, Sandeep K, Aceves, Seema S, Chehade, Mirna, Spergel, Jonathan M, Falk, Gary W, Meltzer, Brian A, Comer, Gail M, Straumann, Alex, Safroneeva, Ekaterina, Group, International EEsAI Study, Achem, Sami R, Arora, Amindra S, Alpan, Oral, Armstrong, David, Attwood, Stephen E, Butterfield, Joseph H, Crowell, Michael D, DeVault, Kenneth R, Drouin, Eric, Enav, Benjamin, Enders, Felicity T, Fleischer, David E, Foxx-Orenstein, Amy, Francis, Dawn L, Guyatt, Gordon H, Harris, Lucinda A, Kagalwalla, Amir F, Kita, Hirohito, Krishna, Murli, Lee, James J, Lewis, John C, Lim, Kaiser, Locke, G Richard, Murray, Joseph A, Nguyen, Cuong C, Orbelo, Diana M, Pasha, Shabana F, Ramirez, Francisco C, Sheikh, Javed, Umar, Sarah B, Weiler, Catherine R, Wo, John M, Wu, Tsung-Teh, and Yost, Kathleen J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Digestive Diseases, Clinical Research, Clinical Trials and Supportive Activities, Prevention, Adolescent, Adult, Aged, Anti-Inflammatory Agents, Dose-Response Relationship, Drug, Eosinophilic Esophagitis, Esophagoscopy, Esophagus, Female, Fluticasone, Humans, Male, Middle Aged, Prognosis, Severity of Illness Index, Young Adult, Index, Variability in Endoscopic Assessment, Instrument, International EEsAI Study Group, Gastroenterology & Hepatology, Clinical sciences
Abstract

Background & aimsEosinophilic esophagitis (EoE) is assessed endoscopically (endoscopic activity), based on grades of edema, rings, exudates, furrows, and strictures (EREFS). We examined variations in endoscopic assessments of severity, developed and validated 3 EREFS-based scoring systems, and assessed responsiveness of these systems using data from a randomized placebo-controlled trial of patients with EoE.MethodsFor the development set, 5 gastroenterologists reviewed EREFS findings from 266 adults with EoE and provided endoscopist global assessment scores (EndoGA, scale of 0 to 10); variation (ΔEndoGA) was assessed using linear regression. We evaluated simple scores (features given arbitrary values from 0 to 3) and developed 2 scoring systems (adjusted score range, 0-100). We then fitted our linear regression model with mean EndoGA to data from 146 adults recruited in centers in Switzerland and the United States between April 2011 and December 2012. For the validation set, we collected data from 120 separate adults (recruited in centers in Switzerland and the United States between May 2013 and July 2014), assessing regression coefficient-based scores using Bland-Altman method. We assessed the responsiveness of our scoring systems using data from a randomized trial of patients with EoE given fluticasone (n=16) or placebo (n=8).ResultsThe distribution of EndoGA values differed among endoscopists (mean ΔEndoGA, 2.6±1.8; range 0-6.6). We developed 2 regression-based scoring systems to assess overall and proximal and distal esophageal findings; variation in endoscopic features accounted for more than 90% of the mean EndoGA variation. In the validation group, differences between mean EndoGA and regression-based scores were small (ranging from -4.70 to 2.03), indicating good agreement. In analyses of data from the randomized trial, the baseline to end of study change in patients given fluticasone was a reduction of 24.3 in simple score (reduction of 4.6 in patients given placebo, P=.052); a reduction of 23.5 in regression-based overall score (reduction of 6.56 in patients given placebo, P=.12), and a reduction of 23.8 (reduction of 8.44 in patients given placebo, P=.11).ConclusionAssessments of endoscopic activity in patients with EoE vary among endoscopists. In an analysis of data from a randomized controlled trial, we found that newly developed scoring systems are no better than simple scoring system in detecting changes in endoscopic activity. These results support the use of a simple scoring system in evaluation of endoscopic activity in patients with EoE. clinicaltrials.gov no: NCT00939263 and NCT01386112.

Published
2019

43. Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles: A Multi-Site Study

Author

Pablo Abonia, J., Aceves, Seema, Almonte, Samuel, Andrews, Rachel, Anvari, Sara, Arrington, Ashley, Arva, Nicoleta, Atkins, Fred, Bailey, Dominique, Berry, Alexis, Besl, Bridget, Bolton, Scott, Bonis, Peter, Book, Wendy, Bray, Kimberly, Brown, Teresa, Burger, Cassandra, Burke, Deirdre, Cahoon, Jonathon, Capocelli, Kelley, Chehade, Mirna, Chiou, Eric, Collins, Margaret, Davis, Carla, Dellon, Evan, DeMarshall, Maureen, DiTommaso, Lauren, Dohil, Ranjan, Eby, Michael, Falk, Gary, Fleischer, David, Foote, Heather, Foss, Kelci, Friedlander, Joel, Fulkerson, Patricia, Furuta, Glenn, Geno, Debra, Gonsalves, Nirmala, Greuter, Thomas, Gupta, Sandeep, Hamilton, Frank, Harris, Kirk, Harris, Jennifer, Hirano, Ikuo, Hiremath, Girish, Holland-Thomas, Nicole, Jacinto, Lea, Kagalwalla, Amir, Kaseta, Timothy, Katzka, David, Keeley, Kaitlin, Khosh-Hemmat, Emad, Khoury, Paneez, King, Eileen, Kliewer, Kara, Klion, Amy, Knowles, Jennifer, Kocher, Kendra, Kodroff, Ellyn, Krischer, Jeffrey, Kyle, Shay, Leung, John, Levy, Meredith, Liacouras, Chris, Mack, Denise, Martin, Lisa, Martin, Ellen, McCright-Gill, Talaya, Menard-Katcher, Paul, Menard-Katcher, Calies, Mendoza, Gabriela, Mingler, Melissa, Minnicozzi, Mike, Muir, Amanda, Mukkada, Vincent, Murray-Petzold, Cristin, Newbury, Robert, Nhu, Quan, Olive, Anthony, Oyibo, Oghenekpaobor (Joel), Paliana, Allisa, Pan, Zhaoxing, Pesek, Robbie, Peterson, Kathryn, Poppendeck, Heidi, Putnam, Philip, Rivera, Fabian, Rothenberg, Marc, Spergel, Amanda Rudman, Sable, Kathleen, Schoepfer, Alain, Scott, Melissa, Sheridan, Rachel, Sinanovic, Selma, Spergel, Jonathan, Strobel, Mary Jo, Sun, Kiki, Tasco, Amy, Tholen, Crystal, Thompson, Katherine, Tomkinson, Tiffany, Tran, Daisy, Tylicki, Alexandra, Urv, Tiina, Wang, Mei-Lun, Wechsler, Joshua, Wershil, Barry, Wheatley, Lisa, Wilkey, Leah, Yang, Guang-Yu, Zalewski, Angelika, Zicarelli, Amy, Shoda, Tetsuo, Collins, Margaret H., Rochman, Mark, Wen, Ting, Caldwell, Julie M., Mack, Lydia E., Osswald, Garrett A., Besse, John A., Haberman, Yael, Aceves, Seema S., Arva, Nicoleta C., Capocelli, Kelley E., Davis, Carla M., Dellon, Evan S., Falk, Gary W., Gupta, Sandeep K., Mukkada, Vincent A., Putnam, Philip E., Spergel, Jonathan M., Wechsler, Joshua B., Furuta, Glenn T., Denson, Lee A., and Rothenberg, Marc E.

Published
2022
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48. Long-Lasting Dissociation of Esophageal Eosinophilia and Symptoms After Dilation in Adults With Eosinophilic Esophagitis

Author

Safroneeva, Ekaterina, Pan, Zhaoxing, King, Eileen, Martin, Lisa J., Collins, Margaret H., Yang, Guang-Yu, Capocelli, Kelley E., Arva, Nicoleta C., Abonia, J. Pablo, Atkins, Dan, Bonis, Peter A., Dellon, Evan S., Falk, Gary W., Gonsalves, Nirmala, Gupta, Sandeep K., Hirano, Ikuo, Leung, John, Menard-Katcher, Paul A., Mukkada, Vincent A., Schoepfer, Alain M., Spergel, Jonathan M., Wershil, Barry K., Rothenberg, Marc E., Aceves, Seema S., and Furuta, Glenn T.

Published
2022
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49. Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell–Fibroblast Crosstalk

Author

Abonia, J. Pablo, Aceves, Seema, Almonte, Samuel, Andrews, Rachel, Arrington, Ashley, Arva, Nicoleta, Atkins, Fred, Bailey, Dominique, Berry, Alexis, Besl, Bridget, Bolton, Scott, Bonis, Peter, Book, Wendy, Bray, Kimberly, Brown, Teresa, Burger, Cassandra, Burke, Deirdre, Cahoon, Jonathon, Capocelli, Kelley, Chehade, Mirna, Collins, Margaret, Davis, Carla, Dellon, Evan, DeMarshall, Maureen, DiTommaso, Lauren, Dohil, Ranjan, Eby, Michael, Falk, Gary, Fleischer, David, Foote, Heather, Foss, Kelci, Friedlander, Joel, Fulkerson, Patricia, Furuta, Glenn, Geno, Debra, Gonsalves, Nirmala, Greuter, Thomas, Gupta, Sandeep, Hamilton, Frank, Harris, Kirk, Harris, Jennifer, Hirano, Ikuo, Hiremath, Girish, Holland-Thomas, Nicole, Jacinto, Lea, Kagalwalla, Amir, Kaseta, Timothy, Katzka, David, Keeley, Kaitlin, Khosh-Hemmat, Emad, Khoury, Paneez, King, Eileen, Kliewer, Kara, Klion, Amy, Knowles, Jennifer, Kocher, Kendra, Kodroff, Ellyn, Krischer, Jeffrey, Kyle, Shay, Leung, John, Levy, Meredith, Liacouras, Chris, Mack, Denise, Martin, Lisa, Martin, Ellen, McCright-Gill, Talaya, Menard-Katcher, Paul, Menard-Katcher, Calies, Mendoza, Gabriela, Mingler, Melissa, Minnicozzi, Mike, Muir, Amanda, Mukkada, Vincent, MurrayPetzold, Cristin, Newbury, Robert, Nhu, Quan, Oyibo, Oghenekpaobor (Joel), Paliana, Allisa, Pan, Zhaoxing, Pesek, Robbie, Peterson, Kathryn, Poppendeck, Heidi, Putnam, Philip, Rivera, Fabian, Rothenberg, Marc, Spergel, Amanda Rudman, Sable, Kathleen, Schoepfer, Alain, Scott, Melissa, Sheridan, Rachel, Sinanovic, Selma, Spergel, Jonathan, Strobel, MaryJo, Sun, Kiki, Tasco, Amy, Tholen, Crystal, Thompson, Katherine, Tomkinson, Tiffany, Tran, Daisy, Tylicki, Alexandra, Urv, Tiina, Wang, Mei-Lun, Wechsler, Joshua, Wershil, Barry, Wheatley, Lisa, Wilkey, Leah, Yang, Guang-Yu, Zalewski, Angelika, Zicarelli, Amy, Shoda, Tetsuo, Wen, Ting, Caldwell, Julie M., Ben-Baruch Morgenstern, Netali, Osswald, Garrett A., Rochman, Mark, Mack, Lydia E., Felton, Jennifer M., Arva, Nicoleta C., Atkins, Dan, Bonis, Peter A., Capocelli, Kelley E., Collins, Margaret H., Dellon, Evan S., Falk, Gary W., Gupta, Sandeep K., Menard-Katcher, Paul A., Mukkada, Vincent A., Putnam, Philip E., Rudman Spergel, Amanda K., Spergel, Jonathan M., Wechsler, Joshua B., Aceves, Seema S., Furuta, Glenn T., and Rothenberg, Marc E.

Published
2022
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50. Mucosal Microbiota Associated With Eosinophilic Esophagitis and Eosinophilic Gastritis

Author

Furuta, Glenn T., Fillon, Sophie A., Williamson, Kayla M., Robertson, Charles E., Stevens, Mark J., Aceves, Seema S., Arva, Nicoleta C., Chehade, Mirna, Collins, Margaret H., Davis, Carla M., Dellon, Evan S., Falk, Gary W., Gonsalves, Nirmala, Gupta, Sandeep K., Hirano, Ikuo, Khoury, Paneez, Leung, John, Martin, Lisa J., Menard-Katcher, Paul, Mukkada, Vincent A., Peterson, Kathryn, Spergel, Jonathan M., Wechsler, Joshua B., Yang, Guang-Yu, Rothenberg, Marc E., and Harris, J. Kirk

Published
2023
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