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1. Machine Learning Approach for Biopsy-Based Identification of Eosinophilic Esophagitis Reveals Importance of Global features

Author

Tomer Czyzewski, Nati Daniel, Mark Rochman, Julie Caldwell, Garrett Osswald, Margaret Collins, Marc Rothenberg, and Yonatan Savir

Subjects
Decision support system, deep convolutional network, digital pathology, eosinophilic esophagitis, small features detection, Computer applications to medicine. Medical informatics, R858-859.7, Medical technology, R855-855.5
Abstract

Goal: Eosinophilic esophagitis (EoE) is an allergic inflammatory condition characterized by eosinophil accumulation in the esophageal mucosa. EoE diagnosis includes a manual assessment of eosinophil levels in mucosal biopsies–a time-consuming, laborious task that is difficult to standardize. One of the main challenges in automating this process, like many other biopsy-based diagnostics, is detecting features that are small relative to the size of the biopsy. Results: In this work, we utilized hematoxylin- and eosin-stained slides from esophageal biopsies from patients with active EoE and control subjects to develop a platform based on a deep convolutional neural network (DCNN) that can classify esophageal biopsies with an accuracy of 85%, sensitivity of 82.5%, and specificity of 87%. Moreover, by combining several downscaling and cropping strategies, we show that some of the features contributing to the correct classification are global rather than specific, local features. Conclusions: We report the ability of artificial intelligence to identify EoE using computer vision analysis of esophageal biopsy slides. Further, the DCNN features associated with EoE are based on not only local eosinophils but also global histologic changes. Our approach can be used for other conditions that rely on biopsy-based histologic diagnostics.

Published
2021
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2. WAO International Scientific Conference (WISC 2016) Abstracts

Author

Jun Bao, Yi-Hui Wang, Quan-Hua Liu, Yi-Xiao Bao, Nurit Azouz, Julie Caldwell, Leanne Ray, Mark Rochman, Melissa Mingler, Matthew Eilerman, Ting Wen, Jocelyn Biagini Myers, Gurjit Khurana Hershey, Leah Kottyan, Lisa Martin, Rothenberg Marc, Victor Gonzalez-Uribe, Jaime Del Rio-Chivardi, Blanca Del Rio-Navarro, Hongfei Lou, Siyuan Ma, Yan Zhao, Feifei Cao, Fei He, Zhongyan Liu, Chengshuo Wang, Claus Bachert, Luo Zhang, Elissa Abrams, Allan Becker, Amit Kandhare, Subhash Bodhankar, Nicole Grossman, Gheorghe Doros, Francine Laden, Anne Fuhlbrigge, Michael Wechsler, Wilson Pace, Barbara Yawn, Elliot Israel, Junehyuk Lee, Frederick Adler, Peter Kim, Yung Feng Huang, Ying Yao Chen, Chiun Yen Pan, Herng Sheng Lee, Michael Khalemsky, David G. Schwartz, Pavel Kolkhir, Dmitry Pogorelov, Nikolay Kochergin, Hirsh Komarow, Michael Young, Robin Eisch, Linda Scott, Dean Metcalfe, Alexander Singer, Andrew Wakeman, Thomas Gerstner, Woo-Jung Song, Ji-Su Shim, Ha-Kyeong Won, Sung-Yoon Kang, Kyoung-Hee Sohn, Byung-Keun Kim, Eun-Jung Jo, Min-Hye Kim, Sang-Heon Kim, Heung-Woo Park, Sun-Sin Kim, Yoon-Seok Chang, Alyn H. Morice, Byung-Jae Lee, Sang-Heon Cho, Kyung-Up Min, Maria Assunta Boscolo, Giulio Brivio, Sergio Bosisio, Nicoletta Manzocchi, Edoardo Pulixi, Giulia Grignani, Eloisia D’Andrea, Massimo Ricci, Elena Passini, Maurizio Italia, Marilyn Urrutia-Pereira, Stefani Fagundes, Vinicius Jardim Oliano, Dirceu Solé, Sadia Benzaquen, Alejandro Aragaki, Ricardo Balestra, Dawn Harden, Danielle Caudell-Stamper, Gilbert Glady, Mark Holbreich, Nataliya Lyakhovska, Igor Kaidashev, Jaromir Bystron, Beata Hutyrova, Galina Balakirski, Luk Vanstreels, Gerda Wurpts, Hans F. Merk, Jens Malte Baron, Johanna Plange, Hans-Peter Rihs, Monika Raulf, Stefani Roeseler, Alberto Tolcachier, Armando Chamorro, Ruth Otero, Joel Brooks, Michael Hess, Jared Benz, Joseph MacDonald, Usma Chatha, Dale Lent, Şükran Köse, Bengü Gireniz Tatar, Gülgün Akkoçlu, İbrahim Çukurova, İlker Ödemiş, Ayşin Kılınç Toker, Abdullahi Hasssan, Abdulrazaq Abdullahi Gobir, Cheol-Woo Kim, Young Hwa Choi, Jeong Hye Lee, Rae Jeong Cho, Yu Ran Nam, Joo Hyun Nam, Woo Kyung Kim, Ivana Filipovic, Zorica Zivkovic, Djordje Filipovic, Dana Shik, Andrew Smith, Wang Yui Hsi, Stuart Friedman, Yonatan Gizaw, Rima Bakhda, Kumail Mohammed, Richard Wasserman, Angela Hague, Deanna Pence, Joanna Rolen, Robert Sugerman, Stacy Silvers, Qurat Kamili, Nadezhda Knauer, Alexandr Zazernyi, Elena Blinova, Daria Demina, Vladimir Kozlov, Komal Agrawal, Sagar Kale, Naveen Arora, Volha Vasilkova, Tatiana Mokhort, William Silvers, Rachel Eisenberg, Rushita Mehta, Arye Rubinstein, Antony Aston, Paul Turner, Monica Ruiz-Garcia, Robert Boyle, Simon Brown, Yael Dinur Schejter, Adi Ovadia, Vy Kim, Brenda Reid, Chaim Roifman, Lana Rosenfield, Ernie Avilla, Laurie Harada, Marilyn Allen, Susan Waserman, Ho Joo Yoon, Gun Woo Koo, Suk-Il Chang, Hye-Ran Yoon, Dong Won Park, Tai Sun Park, Ji-Yong Moon, Tae Hyung Kim, Jang Won Sohn, Dong Ho Shin, Tsici Jorjoliani, Lia Jorjoliani, Nino Adamia, Nona katamadze, Deepika Ramachandra, Liana Jorjoliani, Rusudan Karseladze, Lali Saginadze, Natalia Chkuaseli, Anna Dolgova, Olga Stukolova, Anna Sudina, Anna Cherkashina, German Shipulin, Richard Rosenthal, Harvey Howe, Paul Knause, Rony Greemberg, Jean Jacques De Bruycker, Isabel Fernandez, Françoise Le Deist, Elie Haddad, Yeong Ho Rha, Kyung Suk Lee, Sun Hee Choi, Herman Tam, Estelle Simons, Elinor Simons, Maria Golebiowska-Wawrzyniak, Katarzyna Markiewicz, Yoram Faitelson, Miguel Stein, Avigdor Mandelberg, Ilan Dalal, Michael Levin, Lelani Hobane, Wisdom Basera, Maresa Botha, Claudia Gray, Heather Zar, Biserka Jovkovska Kjaeva, Zoran Arsovski, Vesna Grivcheva-Panovska, Adeyinka Odebode, Adedotun Adekunle, Peter Adeonipekun, Ebenezer Farombi, Nadezhda Camacho-Ordoñez, Alejandrina Josefina Martinez-Vázquez, María de la Luz H. García-Cruz, Qi Tan, Rui Min, Guan-qun Dai, Wei-Ping Xie, Huang Mao, Hong Wang, Rakesh Yadav, Sneha Singh, Divya Yadav, Ekaterina Khaleva, Henry T. Bahnson, Amber Franz, Lene Heise Garvey, Nicola Jay, Rubaiyat Haque, Adam Fox, Gideon Lack, George du Toit, Snezana Radic, Branislava Milenkovic, Ana Neskovic, Ljiljana Danojevic, Liat Nachshon, Michael Goldberg, Michael Levy, Yitzhak Katz, Arnon Elizur, Cristine Rosario, Juliana Kasper, Herbeto Chong-Neto, Carlos Riedi, Nelson Rosario, Michael B. Levy, Ronly Har-Even, Mor Carmel, Michael R. Goldberg, Maia Kherkheulidze, Nani Kavlashvili, Eka Kandelaki, Nino Adamai, Irma Ubiria, Andrea Burke, Monika Kastner, Denica Zheleva, Razvigor Darlenski, Konstantinos Bozinakis, Anastasios Kriebardis, Sofia Styliara, Aikaterini Karastathi, Nikolaos Farmakas, Maria Luiza Kraft Kohler Ribeiro, Ana Carolina Barcellos, Hannah Gabriele Ferreira Silva, Luís Henrique Mattei Carletto, Marcela Carolina Bet, Nathalia Zorze Rossetto, Nelson Augusto Rosario, Herberto Jose Chong-Neto, Fernanda Valença, Marina Novaes, Mariana Gomes, Carla Seifert, Alfredo Neto, Flavia Loyola, José Rios, Tatiana Silva, Aline Neves, Oznur Abadoglu, Bilun Gemicioglu, Hasan Bayram, Arif Cimrin, Levent Akyildiz, Aykut Cilli, Hakan Gunen, Tevfik Ozlu, Mecit Suerdem, Esra Uzaslan, Zeynep Misirligil, Snezana Ristic-Stojanovic, A. Milicevic, A. Milenkovic, Jelena Cvejic, Jelena Jankovic, Sanja Dimic-Janjic, Natasa Djurdjevic, Vladyslava Barzylovych, Tetiana Umanets, Anastasia Barzylovych, Karyn Winkler, Jessica Margarinos, Dylan Martin, Maja Nowakowski, Rauno Joks, Tsili Zangen, Olga Bernadsky, Mona Boaz, Gratiana Hermann, Rachel Aviv, Olga Kuperboim, Larisa Ramichanov, Efrat Broide, Raanan Shamir, Noam Zevit, Ron Shaoul, Alex Fich, Arie Levine, Isaac Melamed, Roopesh Singh Gangwar, Yael Minai-Fleminger, Mansour Seaf, Amichai Gutgold, Aarti Shikotra, Anoop Chauhan, Stephen Holgate, Peter Bradding, Peter Howarth, Ron Eliashar, Neville Berkman, Francesca Levi-Schaffer, Sung-il Woo, Betul Celik, Tangul Bulut, Arzu Didem Yalcin, Luiz Querino Caldas, Ronit Confino-Cohen, Yossi Rosman, Arnon Goldberg, Oded Breuer, Roopesh Singh, Ahlam Barhoum, Eitan Kerem, Tatiana Slavyanskaya, Revaz Sepiashvili, Elena A. Blinova, Ekaterina A. Pashkina, Marina I. Leonova, Vera M. Nepomnyaschikh, Darya V. Demina, Vladimir A. Kozlov, Revital Shamri, Kristen M. Young, Peter F. Weller, Rodolfo de Paula Vieira, Manoel Carneiro Oliveira-Junior, Nilsa Regina Damasceno-Rodrigues, Fernanda Magalhães Arantes-Costa, Milton Arruda Martins, Ana Paula Ligeiro Oliveira, Alfred Bernard, Antonia Sardella, Catherine Voisin, Simon Royce, Hamish Philpott, Sanjay Nandurkar, Francis Thien, Peter Gibson, Rodolfo Bianchini, Franziska Roth-Walter, Anna Ohradanova-Repic, Gerlinde Hofstetter, Ina Herrmann, Maria Isabel Carvalho, Karin Hufnagl, Erika Bajna, Georg Roth, Hannes Stockinger, Erika Jensen-Jarolim, Meital Almog, Aharon Kessel, Larisa Apov, Carlos Sanchez Salguero, Alvaro Sanchez Chacon, Abbos Nazarov, Shaxbos Ergashev, Irina Nesterova, Svetlana Kovaleva, Galina Chudilova, Ludmila Lomtatidze, Sarah De Schryver, Alizee Dery, Ann Clarke, Kari Nadeau, Kimberly Weatherall, Celia Greenwood, Denise Daley, Yuka Asai, Moshe Ben-Shoshan, Irina Balmasova, Elena Malova, Stefanie Wagner, Luis F. Pacios, Michael Wallner, Markus Wiederstein, Anna E. Tevs, Nataly Tataurshchikova, Baigalmaa Sangidorj, Anna Ronzhina, Manana Chikhladze, Oliver F. Wirz, Willem van de Veen, David Mirer, Hideaki Morita, Can Altunbulakli, Sebastian L. Johnston, Nicholas Glanville, Nikolaos G. Papadopoulos, Cezmi A. Akdis, Mübeccel Akdis, Avner Reshef, Marc Riedl, Vesna Grivcheva Panovska, Dumitru Moldovan, James Baker, William H. Yang, Sladjana Andrejevic, Richard F. Lockey, Roman Hakl, Shmuel Kivity, Luca Bellizzi, Joseph R. Harper, Anurag Relan, and Marco Cicardi

Subjects
Immunologic diseases. Allergy, RC581-607
Published
2017
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4. Supplementary Data from Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity

Author

Ariel Munitz, Asaf Madi, Tamar Geiger, Hua Yu, Melissa J. Davis, Marc E. Rothenberg, Gabrielle T. Belz, Nicolas Jacquelot, Neta Erez, Motti Gerlic, Shlomo Tsuriel, Ophir Shani, Yaara Gordon, Inbal Hazut, Shmuel Avlas, Avishay Dolitzky, Perri Rozenberg, Julie Caldwell, Soroor Hediyeh-zadeh, Michal Itan, Chunyan Zhang, Lir Beck, Shai Dulberg, and Sharon Grisaru-Tal

Abstract

Supplementary Methods and Data- Changes are unmarked

Published
2023
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5. Data from Metastasis-Entrained Eosinophils Enhance Lymphocyte-Mediated Antitumor Immunity

Author

Ariel Munitz, Asaf Madi, Tamar Geiger, Hua Yu, Melissa J. Davis, Marc E. Rothenberg, Gabrielle T. Belz, Nicolas Jacquelot, Neta Erez, Motti Gerlic, Shlomo Tsuriel, Ophir Shani, Yaara Gordon, Inbal Hazut, Shmuel Avlas, Avishay Dolitzky, Perri Rozenberg, Julie Caldwell, Soroor Hediyeh-zadeh, Michal Itan, Chunyan Zhang, Lir Beck, Shai Dulberg, and Sharon Grisaru-Tal

Abstract

The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets of patients, understanding the activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastases are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein–coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated antitumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing antitumorigenic eosinophil activities. Specifically, TNFα/IFNγ–activated eosinophils facilitated CD4+ and CD8+ T-cell infiltration and promoted antitumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt antitumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics.Significance:These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer.

Published
2023
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6. Genome-wide admixture and association analysis identifies African ancestry specific risk loci of eosinophilic esophagitis in African American

Author

Yadu Gautam, Julie Caldwell, Leah Kottyan, Mirna Chehade, Evan S. Dellon, Marc E. Rothenberg, Tesfaye B. Mersha, Joshua Wechsler, Carla Davis, Glenn Furuta, Paneez Khoury, Seema Aceves, Sandeep K. Gupta, Jonathan Spergel, John Leung, Paul Menard-Katcher, Gary Falk, Ikuo Hirano, Nirmala Prabu Gonsalves, and Kathryn Peterson

Subjects
Immunology, Immunology and Allergy
Abstract

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease. Multiple genetic risk factors linked to EoE have been identified; however, these studies have been primarily focused on populations of European ancestry. There is a lack of studies leveraging the genetic architecture of Black or African American (AA) populations for the identification of loci involved in EoE susceptibility. Herein, we present admixture mapping (AM) and genome-wide association analysis (GWAS) of EoE using the participants of AA populations.We conducted AM and GWAS of EoE using 137 EoE cases and 1465 healthy controls from AA population. Samples were genotyped using the Multi-Ethnic Genotyping Array (MEGA). Genotype imputation was carried out with the CAAPA reference panel using the Michigan Imputation Server. Global and local ancestry inference was carried out using RFMix v2, followed by fine-mapping analysis based on imputed genotypes, and RNAseq analysis. After standard quality control filtering, over 6,000,000 variants were tested by logistic regression adjusted for sex, age, and global ancestry.Global African ancestry proportion was found to be significantly lower among cases than controls (0.751 vs. 0.786, p-value = 0.012). Case-only AM identified four significant loci (9p13.3, 12q24.22-23, and 15q11.2) associated with EoE, two of which (12q24.22-23 and 9p13.3) were further replicated in the case-control analysis. At the two loci (12q24.23 and 9p13.3), the associations were observed for excess African ancestry. Fine mapping and multi-omic functional annotations prioritized the variants rs11068264 (FBXW8) and rs7307331 (VSIG10) at 12q24.23 and rs2297879 (ARHGEF39) at 9p13.3. GWAS identified one genome-wide significant locus at chromosome 1p22.3 (rs17131726, p-value = 2.39e-27, DDAH1) and 10 other suggestive loci including FAM179A (rs145050353), SCAND3 (rs56100858), TBC1D13 (rs114834583), MT2 (rs34800257) and PCSK2 (rs75293413) associated with EoE at p-value1×10We have identified an African ancestry specific genetic susceptibility locus DDAH1 at 1p22.3, 1p22.3, 9p13.3, and 12q24.23, through GWAS and admixture mapping for EoE in AA, providing evidence of ancestral specific inheritance of EoE. These findings highlight the need of independent genetic studies of different ancestries for EoE.

Published
2022

11. Skin is in. Laser therapy in primary care

Author

Julie, Caldwell and Susan, Martin

Subjects
Primary Health Care, Humans, Rejuvenation, Nurse Practitioners, Laser Therapy, Telangiectasis, Surgery, Plastic, Hair Removal, Skin Aging
Published
2009

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