Surgical Research Lab Faculty

Xiaoxin Luke Chen, MD, PhD
Director, Surgical Research Lab, Department of Surgery
Professor of Surgery, CMSRU
Associate Research Director, MD Anderson Cancer Center at Cooper
Professor, Coriell Institute for Medical Research
E&R Building Room 386
chen-xiaoxin@cooperhealth.edu

I have two major research directions with grant support from the National Institutes of Health (CA244236 and AA030026):

• Preclinical targeted therapy of esophageal squamous cell carcinoma (ESCC): We are particularly interested in developing targeted therapy of ESCC in vitro and in vivo with specific molecular alterations. These studies can be potentially translated into clinical studies. Our current target is the Nrf2 signaling pathway.
• Molecular mechanism and prevention of alcohol and tobacco-associated esophageal cancer: The goal of this research direction is to understand how alcohol and tobacco carcinogens may cause esophageal cancer, and how to prevent this type of cancer. Both pharmacological (pharmaceutical and dietary agents) and genetic approaches are employed to elucidate the mechanism of oro-esophageal carcinogenesis and design preventive strategies for clinical studies.

Publications

Yahui Li, Zhaohui Xiong, Chorlada Paiboonrungruang, Boopathi Subramaniyan, Curt Balch, David D. Shersher, Francis Spitz and Xiaoxin Chen. Lymphatic Metastasis of Esophageal Squamous Cell Carcinoma: The Role of NRF2. Cancers [publication details forthcoming].

Xiaoxin Chen, Qing Cheng, Guo-Fang Zhang.
Elevated propionate and its association with neurological dysfunctions in propionic acidemia. Frontiers in Molecular Neuroscience, 18 March 2025, Sec. Brain Disease Mechanisms, Volume 18-2025. https://doi.org/10.3389/fnmol.2025.1499376

Jennifer Williams, MD, Kristen Knapp, MD, Brian Zilberman, MD, Andrew Lin, MD, Vincent Verchio, MD, Zeus Antonello, PhD, Ping Zhang, PhD, Drew Delong, VMD, Francis Spitz, MD, Julieta E. Barroeta, MD, Xiaoxin Chen, MD, and David Shersher, MD.
Adipose-Derived Stem Cells Prevent Anastomotic Leak: A Porcine Ischemic Esophagectomy Model,
Journal of Surgical Research, 2025-01-01, Volume 305, Pages 65-79, Copyright © 2024 Elsevier Inc., https://doi.org/10.1016/j.jss.2024.10.054

You Wang, Suhong Zhu, Wentao He, Hannah Marchuk, Eva Richard, Lourdes R. Desviat, Sarah P. Young, Dwight Koeberl, Takhar Kasumov, Xiaoxin Chen & Guo-Fang Zhang.
The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia. Basic Research in Cardiology, July 11, 2024. https://link.springer.com/article/10.1007/s00395-024-01066-w

He W, Marchuk H, Koeberl D, Kasumov T, Chen X, Zhang GF. Fasting alleviates metabolic alterations in mice with propionyl-CoA carboxylase deficiency due to Pcca mutation. Commun Biol 2024; 7, 659. https://doi.org/10.1038/s42003-024-06362-8.

Paiboonrungruang C, Xiong Z, Lamson D, Li Y, Bowman B, Chembo J, Huang C, Li J, Livingston EW, Frank JE, Chen V, Li Y, Weissman B, Yuan H, Williams KP, Major MB, Chen X. Small Molecule Screen Identifies Pyrimethamine as an Inhibitor of NRF2-driven Esophageal Hyperplasia. Redox Biology 2023; 67:102901.

Knapp K, Verchio V, Coburn-Flynn O, Li Y, Xiong Z, Morrison JC, Shersher DD, Spitz F, Chen X. Exploring cell competition for the prevention and therapy of esophageal squamous cell carcinoma. Biochem Pharmacol. 2023 Aug;214:115639.

Li Y, Cheng Q, Xiong Z, Paiboonrungruang C, Adekoya T, Li Y, Chen X. Lymphatic Drainage System and Lymphatic Metastasis of Cancer Cells in the Mouse Esophagus. Dig Dis Sci. 2023 Mar;68(3):803-812.

Xiong Z, Chen X. NRF2 Controls the Competitive Fitness of Squamous Epithelial Cells in the Mouse Esophagus. Cell Mol Gastroenterol Hepatol. 2022 Nov 6:S2352-345X(22)00221-1.

Paiboonrungruang C, Simpson E, Xiong Z, Huang C, Li J, Li Y, Chen X. Development of targeted therapy of NRF2high esophageal squamous cell carcinoma. Cell Signal. 2021;86:110105.

For a complete list, visit my bibliography at the National Library of Medicine or The Chen Lab at NCCU.

Francis Spitz, MD, FACS
Chief, Department of Surgery
Head, Division of General Surgery
Cooper University Health Care
Deputy Director, MD Anderson Cancer Center at Cooper
Professor of Surgery, CMSRU
Sheridan Pavilion 411, Camden, NJ 08103
spitz-francis@cooperhealth.edu

I am interested in translational cancer research aiming at developing novel therapy for human cancer.

• NRF2 activation in lung and head & neck cancer

Publications

Zena Saleh, Matthew C. Moccia, Zachary Ladd, Upasana Joneja, Yahui Li, Francis Spitz, Young Ki Hong, and Tao Gao. Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation. Int. J. Mol. Sci. 2024, 25, 1331. https://doi.org/10.3390/ijms25021331.

Knapp K, Verchio V, Coburn-Flynn O, Li Y, Xiong Z, Morrison JC, Shersher DD, Spitz F, Chen X. Exploring cell competition for the prevention and therapy of esophageal squamous cell carcinoma. Biochem Pharmacol. 2023 Aug;214:115639.

For a complete list, click here.

Young Ki Hong, MD, MPH
Assistant Director, Surgical Research Lab
Cooper University Health Care
Assistant Professor of Surgery, CMSRU
Sheridan Pavilion 411, Camden, NJ 08103
hong-young@cooperhealth.edu

I am interested in translational cancer research aiming at developing novel therapy for human cancer.

• Epigenetic therapy for pancreatic neuroendocrine tumor (PNET)
• HIPEC with epigenetic drugs for peritoneal carcinomatosis of colorectal cancer

Publications

Zena Saleh, Matthew C. Moccia, Zachary Ladd, Upasana Joneja, Yahui Li, Francis Spitz, Young Ki Hong, and Tao Gao. Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation. Int. J. Mol. Sci. 2024, 25, 1331. https://doi.org/10.3390/ijms25021331.

Zhu C, Sandilos G, Williamson J, Emery R, Platoff R, Joneja U, Acharya NK, Lin A, Badach J, Zilberman B, Zadzo J, Jelinek J, Zhang P, Hong YK. Novel treatment strategy of targeting epigenetic dysregulation in pancreatic neuroendocrine tumors. Surgery. 2023 Apr;173(4):1045-1051.

Hong YK, Li Y, Wang X, Pandit H, Zheng Q, Yu Y, Shi X, Chen Y, Tan M, Pulliam Z, Bhutiani N, Lin A, Badach J, Zhang P, Martin RCG. Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma. Clin Transl Immunology. 2022 Nov 28;11(12).

Hong YK, Li Y, Pandit H, Li S, Pulliam Z, Zheng Q, Yu Y, Martin RCG. Epigenetic modulation enhances immunotherapy for hepatocellular carcinoma. Cell Immunol. 2019 Feb;336:66-74

Madeline B. Torres, MD
Assistant Professor of Surgery
Cooper Medical School of Rowan University
Division of Surgical Oncology, Department of Surgery
Cooper University Health Care
MD Anderson Cancer Center at Cooper
Sheridan pavilion 411, Camden, NJ 08103
torres-madeline@cooperhealth.edu

I am a surgical oncologist committed to advancing the care of patients with gastrointestinal and soft tissue malignancies. I am interested in identifying and developing novel tumor markers and targets for solid tumors, specifically soft tissue sarcomas and pancreatic adenocarcinoma.

Selected Publications

Gingrich A, Wangsiricharoen S, Torres MB, Ravi V, Ratan R, Keung EZ, Scally CP, Lazar AJ, Wang WL, Rolan CL, Hunt KK, Yu W, Torres KE. Clinical Variables Influencing Outcomes in Patients with Atypical Intradermal Smooth Muscle Neoplasms (Formerly Cutaneous Leiomyosarcomas): Single-Institution study of 95 Surgical Patients. Ann Surg Oncol. 2024 Nov; 31(12):7950-7956. doi: 10.1245/s10434-024-15528-x. 

Li N, Torres MB, Spetz MR, Wang R, Peng L, Tian M, Dower CM, Nguyen R, Sun M, Tai CH, de Val N, Cachau R, Wu X, Hewitt SM, Kaplan RN, Khan J, St Croix B, Thiele CJ, Ho M. CAR T cells targeting tumor-associated exons of glypican 2 regress neuroblastoma in mice. Cell Reports Med. June 2021. doi:10.1016/j.xcrm. 2021.100297 

Li D, Li N, Zhang Y-F, Fu H, Feng M, Schneider D, Su L, Wu X, Zhou J, Mackay S, Kramer J, Duan Z, Yang H, Kolluri A, Hummer AM, Torres MB, Zhu H, Hall MD, Luo X, Chen J, Wang Q, Abate-Daga D, Dropublic, Hewitt SM, Orentas RJ, Greten TF, Ho M. Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice. Gastroenterology. 2020 Jun;158(8):2250- 2265.e20. doi: 10.1053/j.gastro.2020.02.011. 

Yan Ma, BS
Lab Manager
Surgical Research Division, Department of Surgery
Cooper University Health Care
E&R Building Room 392, 401 Haddon Avenue, Camden, NJ 08103
ma-yan@cooperhealth.edu

I am an accomplished lab manager with many years of experience in this capacity, and I have co-authored 52 cancer research papers. Throughout my career, my foremost responsibility is to oversee the seamless functioning of the laboratory and off steadfast support to our team of scientists, students, residents, and other lab members. In addition, I support histology experiments in the lab.

Lois Marcolongo, BA
Administrative Assistant
Surgical Research Lab, Department of Surgery
Cooper University Health Care
E&R Building Room 392
marcolongo-lois@cooperhealth.edu

I am pleased to serve the Cooper Surgical Research Division as Administrative Assistant, since the research work performed by our scientists is so important to patient outcomes. Previously, I served as an Executive Assistant in Cooper’s Graduate Medical Education office, where the interactions with the residents and fellows, and even CMSRU medical students, was an uplifting experience.

Prior to my Cooper service, I was employed for many years as Senior Program Coordinator at the American Association for Cancer Research (AACR) in Philadelphia, and internationally at the UN Agricultural Agencies (FAO & IFAD) in Rome, Italy. In all positions, my BA degree in Modern Languages from Villanova University was put to good use and enhanced my experiences.

Weam Elbezanti, PharmB, MS, PhD
Assistant Professor
Cooper Medical School of Rowan University
Scientist - Clinical Research
Surgical Research Lab, Department of Surgery
Cooper University Health Care
E&R Building, Room 391, 401 Haddon Ave, Camden, NJ 08103
elbezanti-weam@cooperhealth.edu

My lab is committed to advancing innovative therapeutic approaches for human cancer, with a particular emphasis on FDA-approved medications that influence epigenetics. I am passionate about translational cancer research, where my primary goal is to pioneer new therapies for human cancer. Specifically, my research focuses on understanding the effects of these medications on chromatin remodeling, gene expression, and the tumor microenvironment.

Grants

New Jersey Health Foundation Grant # PC 52-25.
February 17, 2025 through February 16, 2026
Targeting Colorectal Cancer Peritoneal Carcinomatosis with Mithramycin A: A Preclinical Evaluation in a Hyperthermic Chemotherapy Model.
 

Publications

Elbezanti, W. O., Challagundla, K. B., & Pandey, M. K. (2024). The study of small RNA sequencing from biological samples (miRNA-seq). In V. J. Carabetta & O. Akintunde (Eds.), High throughput gene screening: Methods and protocols (pp. 175–188). Humana. DOI: https://doi.org/10.1007/978-1-0716-4192-7_10

Al-Odat OSF, Elbezanti WO, Gowda K, Srivastava S, Amin SG, Jonnalagadda SC, Budak-Alpdogan T, Pandey MK. KS18, a Mcl-1 inhibitor, improves the effectiveness of bortezomib and overcomes resistance in refractory multiple myeloma by triggering intrinsic apoptosis. Front Pharmacol. 2024; 15:1436786. doi: 10.3389/fphar.2024.1436786.

Bhowmick K, von Suskil M, Al-Odat OS, Elbezanti WO, Jonnalagadda SC, Budak-Alpdogan T, Pandey MK. Pathways to therapy resistance: The sheltering effect of the bone marrow microenvironment to multiple myeloma cells. Heliyon. 2024 Jun 14;10(12) . doi: 10.1016/j.heliyon.2024.e33091. PMID: 39021902; PMCID: PMC11252793.

Weam Othman Elbezanti, Kishore B. Challagundla, Jonnalagadda, Subash, Tulin Budak-Alpdogan, and Manoj K. Pandey. Past, Present and a Glance into the Future of Multiple Myeloma Treatment. Pharmaceuticals. 2023 Mar 8;16(3):415. doi: 10.3390/ph16030415. PMID: 36986514; PMCID: PMC10056051.

Elbezanti WO, Al-Odat OS, Chitren R, Singh JK, Srivastava SK, Gowda K, Amin S, Robertson GP, Nemmara VV, Jonnalagadda SC, Budak-Alpdogan T, Pandey MK. Development of a novel Bruton's tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cells. Front Pharmacol. 2022 Sep 9;13:894535. doi: 10.3389/fphar.2022.894535. PMID: 36160379; PMCID: PMC9500300.

Al-Odat O, von Suskil M, Chitren R, Elbezanti W, Srivastava S, Budak-Alpddogan T, Jonnalagadda S, Aggarwal B, Pandey M. Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma. Front Pharmacol. 2021 Jul 19;12:699629. doi: 10.3389/fphar.2021.699629. Erratum in: Front Pharmacol. 2021 Aug 31;12:758130. PMID: 34349655; PMCID: PMC8327170.

Lin A, Elbezanti WO, Schirling A, Ahmed A, Van Duyne R, Cocklin S, Klase Z. Alprazolam Prompts HIV-1 Transcriptional Reactivation and Enhances CTL Response Through RUNX1 Inhibition and STAT5 Activation. Front Neurol. 2021 Jul 22;12:663793. doi: 10.3389/fneur.2021.663793. PMID: 34367046; PMCID: PMC8339301.

Von Suskil M, Sultana KN, Elbezanti WO, Al-Odat OS, Chitren R, Tiwari AK, Challagundla KB, Srivastava SK, Jonnalagadda SC, Budak-Alpdogan T, Pandey MK. Bruton's Tyrosine Kinase Targeting in Multiple Myeloma. Int J Mol Sci. 2021 May 27;22(11):5707. doi: 10.3390/ijms22115707. PMID: 34071917; PMCID: PMC8198777.

Elbezanti W, Lin A, Schirling A, Jackson A, Marshall M, Duyne RV, Maldarelli F, Sardo L, Klase Z. Benzodiazepines Drive Alteration of Chromatin at the Integrated HIV-1 LTR. Viruses. 2020 Feb 9;12(2):191. doi: 10.3390/v12020191. PMID: 32050449; PMCID: PMC7077212.

Sardo L, Lin A, Khakhina S, Beckman L, Ricon L, Elbezanti W, Jaison T, Vishwasrao H, Shroff H, Janetopoulos C, Klase ZA. Real-time visualization of chromatin modification in isolated nuclei. J Cell Sci. 2017 Sep 1;130(17):2926-2940. doi: 10.1242/jcs.205823. Epub 2017 Jul 25. PMID: 28743737; PMCID: PMC5612227.

Sardo L, Vakil PR, Elbezanti W, El-Sayed A, Klase Z. The inhibition of microRNAs by HIV-1 Tat suppresses beta catenin activity in astrocytes. Retrovirology. 2016 Apr 8;13:25. doi: 10.1186/s12977-016-0256-y. PMID: 27060080; PMCID: PMC4826512.

Joglekar M, Elbezanti WO, Weitzman MD, Lehman HL, van Golen KL. Caveolin-1 mediates inflammatory breast cancer cell invasion via the Akt1 pathway and RhoC GTPase. J Cell Biochem. 2015 Jun;116(6):923-33. doi: 10.1002/jcb.25025. Erratum in: J Cell Biochem. 2017 May;118(5):1273. PMID: 25559359.

Tao Gao, PhD
Scientist - Clinical Research
Surgical Research Lab, Department of Surgery
Cooper University Health Care
Assistant Professor of Surgery, CMSRU
E&R Building, Room 388, 401 Haddon Ave, Camden, NJ 08103
gao-tao@cooperhealth.edu

Research interest

My major research interest at Cooper Surgical Research Lab is to build a platform to develop novel therapies for pancreatic neuroendocrine tumor (PNET). PNET is a historically rare tumor, with an annual incidence of 0.32 per 100,000. As a result, these malignancies have a relative paucity of knowledge surrounding their treatment. Despite clinically available strategies, the rate of 5-year survival significantly decreases by stage – 60-100% for localized disease, 40% for regional disease, and 25% for metastatic disease. There remains a significant clinical need to develop novel therapy for this disease.

Recent genomic and epigenomic studies have shown that PNETs are heterogenous in origin based on α-like, β-like islet cells of Langerhans, or intermediate type with associated ARX+ or PDX1+ transcriptional promotor hypermethylation profiles. Hypermethylation of promoter regions of tumor suppressor genes results in decreased expression of those genes and subsequent promotion of tumor growth. Previous research has shown hypermethylation of tumor suppressors in PNETs is mainly due to DNA methyltransferase 1 (DNMT1) overexpression. Epigenetic drugs activate anti-tumor immunity by inducing viral mimicry in tumor cells, regulate immune cells trafficking and infiltration, and reactivate exhausted immune cells.

Our research plan is to build a platform to develop novel epigenetic drugs which synergize with chemotherapy for PNET treatment through upregulation of tumor suppressor and immunomodulatory genes, via various studies including biochemistry, cell culture, next-generation sequencing, xenograft animal modeling, and systematic profiling of PNET patient samples. We will use this platform to provide basic research training to both Cooper medical residents and Rowan medical students, helping them to better understand the translational aspect of preclinical findings from basic research in clinical applications.

Grants

I have major research direction with grant support from the New Jersey Health Foundation (PC 54-24):

• Development of Novel NRF2 Inhibitors for NRF2Mut ESCC
   

Publications

Zena Saleh, Matthew C. Moccia, Zachary Ladd, Upasana Joneja, Yahui Li, Francis Spitz, Young Ki Hong, and Tao Gao. Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation. Int. J. Mol. Sci. 2024, 25, 1331. https://doi.org/10.3390/ijms25021331.

Gao T, Wright-Jin EC, Sengupta R, Anderson JB, Mendelsohn CL, and Heuckeroth RO.  *Cell-autonomous retinoic acid receptor signaling alters enteric nervous system development with stage-specific effects in mice. JCI Insight 2021;6(10):e145854. https://doi.org/10.1172/jci.insight.145854. *Editors’ highlight

Wright CM, Schneider S, Smith-Edwards KM, Mafra F, Leembruggen AJL, Gonzalez MV, Kothakapa DR, Anderson JB, Maguire BA, Gao T, et al. ScRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3. Cell Mol Gastroenterol Hepatol (2021) Jan 11;S2352-345X(20)30213-7

Gao T, Mckenna B, Li C, et al. Pdx1 maintains β-cell identity and function by repressing an α-cell identity. Cell Metabolism (2014) Feb 4,19(2):259-71

Gao T, Zhou D, Yang C, et al. *Hippo Signaling Regulates Differentiation and Maintenance in the Exocrine Pancreas. Gastroenterology (2013) 144(7):1543-1553 *Cover story

Srinivasan M, Dodds C, Ghanim H, Gao T, et al. Maternal obesity and fetal programming: effects of a high-carbohydrate nutritional modification in the immediate postnatal life of female rats. Am J Physiol Endocrinol Metab (2008) 295(4):E895-903.

Gao T, O'Brian MR. Control of DegP-dependent degradation of c-type cytochromes by heme and the cytochrome c maturation system in Escherichia coli. J Bacteriol. 2007 Sep;189(17):6253-9

Gao T, O'Brian MR. Iron-dependent cytochrome c1 expression is mediated by the status of heme in Bradyrhizobium japonicum. J Bacteriol. 2005 Aug;187(15):5084-9

Hyun-Kyung Ko, PhD
Scientist-Clinical Research, MD Anderson Cancer Center at Cooper
Cooper University Health Care
E&R Building, Room 386, 401 Haddon Ave, Camden, NJ 08103
ko-hyunkyung@cooperhealth.edu

Research interest

I have been conducting cancer research for over a decade, focusing on understanding the mechanisms of cancer progression and the identification of new targets for treatment-resistant cancers at advanced stage. I received my PhD in biophysics from Roswell Park Graduate Division of SUNY Buffalo. My graduate work focused on the role of a scaffolding protein in cell migration and prostate cancer metastasis. Post-graduation, I pursued a postdoctoral fellowship in the laboratory of Dr. Nima Sharifi in Cleveland Clinic, where I investigated the mechanism of treatment resistant prostate cancer with a focus on steroid metabolism pathways. I then moved to Oregon Health & Science University as a junior faculty and led research projects related to drug discovery targeting bone metastasis, tumor heterogeneity, and target discovery for drug resistant prostate cancer. In 2024, I joined Cooper University Health Care as a Scientist -Clinical Research in the department of MD Anderson Cancer Center at Cooper, where I continue my research career with primary responsibility for conducting translational cancer research. I am also engaged in a research program in the surgery department as a research mentor for Cooper medical residents, guiding them through their research projects and providing expertise. For our research, I work closely with Dr. Shumei Song to manage and implement all aspects of the study. Our research is currently focused on investigating the mechanisms of gastric cancer progression and metastasis and the identification of novel drug targets for advanced gastric cancer. We use a wide variety of systems, including cell lines, organoid samples, patient derived xenograft mouse models, human samples through Cooper Biobank, and clinical data. The long-term objective of our research is to develop novel and effective therapeutic strategies to treat cancers at advanced stage.

Publications

Changhui Xue, Hyun-Kyung Ko, Kasen Shi, Janet Pittsenbarger, Lucien Vu Dao, Kaiyo Shi, Maximilian Libmann, Hao Geng, David Z. Qian. Understanding the development of enzalutamide resistance based on a functional single-cell approach. 2025. The prostate, in press.

Hao Geng, Hyun-Kyung Ko, Janet Pittsenbarger, Christopher T Harvey, Changhui Xue, Qiong Liu, Sadie Wiens, Sushant K Kachhap, Tomasz M Beer, David Z Qian. HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-Inhibition. 2021. Front Cell Dev Biol, 9: 724059. Role: Co-first author.

Zhang L, Pattanayak A, Li W, Ko HK, Fowler G, Gordon R, Bergan R. A Multifunctional Therapy Approach for Cancer: Targeting Raf1- Mediated Inhibition of Cell Motility, Growth, and Interaction with the Microenvironment. 2019. Mol Cancer Ther, 19(1):39-51.

Ziqi Zhu, Yoon-Mi Chung, Olga Sergeeva, Vladimir Kepe, Michael Berk, Jianneng Li, Hyun-Kyung Ko, Zhenfei Li, Marianne Petro, Frank P DiFilippo, Zhenghong Lee, Nima Sharifi. Loss of dihydrotestosterone-inactivation activity promotes prostate cancer castration resistance detectable by functional imaging. 2018. J Biol Chem, 293(46):17829-17837.

Hyun-Kyung Ko, Michael Berk, Yoon-Mi Chung, Belinda Willard, Rohan Bareja, Mark Rubin, Andrea Sboner, Nima Sharifi. Loss of an androgen-inactivating and isoform-specific HSD17B4 splice form enables emergence of castration-resistant prostate cancer. 2018. Cell Reports, 22(3):809-819.

Hyun-Kyung Ko, Li-wu Guo, Bing Su, Lingqiu Gao and Irwin H. Gelman. Suppression of Chemotaxis by SSeCKS via Scaffolding of Phosphoinositol Phosphates and the Recruitment of the Cdc42 GEF, Frabin, to the Leading Edge. 2014. PLoS One, 9(10):e111534.

Bing Su, Lingqiu Gao, Catherine Baranowski, Bryan Gillard, Jianmin Wang, Ryan Ransom, Hyun-Kyung Ko, and Irwin H. Gelman. A genome-wide RNAi screen identifies FOXO4 as a metastasis-suppressor through counteracting PI3K/AKT signal pathway in prostate cancer. 2014. PLoS One, 9(7):e101411

Hyun-Kyung Ko, Shin Akakura, Jennifer Peresie, David W. Goodrich, Barbara A. Foster, and Irwin H. Gelman. A Transgenic model for early prostate metastasis to the lymph nodes. 2014. Cancer Research, 74(3):945-953.

Shumei Song, MD, PhD
Director, Translational GI Cancer Research, MD Anderson Cancer Center at Cooper
Professor, Department of Surgery, CMSRU
Professor, Coriell Institute for Medical Research and Camden Cancer Research Center
song-shumei@cooperhealth.edu

The Song lab’s current focus is to understand how aberrant stem cell signaling including Hippo/YAP1, Notch and TGF-β signaling play a role in the pathogenesis of esophageal and gastric cancers and how deregulation of these pathways drives cancer stem cells (CSCs) traits, tumor progression, therapy resistance and even metastasis; and how Hippo/YAP1 and SOXs affect tumor immunosuppressive microenvironments. The lab strives to discover novel targets and immunotherapies by elucidating tumor-immune interactions and tumor microenvironment from patient samples. Dr. Song and her team are working to build the functional translational GI cancer research platforms (PDXs, organoids, stem cells, patient-derived cancer cells and fibroblasts, TMA etc) for translational and preclinical studies aiming to translate discoveries from the laboratory into new therapies in the clinics.

The Song lab has several research interests with grant support from the National Institute of Health (NIH) and Department of Defense (DODs)

• Molecular mechanisms and functional role of Hippo/YAP/TAZ in mediating CSCs traits, therapy resistance and metastases in gastrointestinal cancers: The goal is to understand how upregulation of YAP1 or TAZ, the two coactivators as well as their transcriptional factors (TEAD1-4) in Hippo signaling in GI tumors contribute to CSCs, therapy resistance and metastases.
• Developing novel therapeutic strategies to target Hippo/YAP/TAZ/TEAD to overcome therapy resistance and metastases by small molecule library screening and drug design; and test their antitumor activities in vitro and in PDXs in vivo models. We believe YAP/TAZ/TEAD inhibitors will be used in combination with chemoradiotherapy and immunotherapy. Our long-term goal is to translate some of these inhibitors into clinical trials.
• Elucidate HippoYAP/SOXs/CSCs mediated tumor immunosuppressive microenvironment and the interaction among tumor cells, macrophage, cancer associated fibroblast (CAFs) and T cells for novel therapeutic strategies.
• Exploring novel immune checkpoints from patients derived metastatic cells/tissues and identify the effective target and immune combination therapies using syngenetic and genetic mouse models.
• Building strong translational GI programs (PDXs, organoids etc) and facilitate novel discoveries from patients’ samples that provide rationale for novel clinical trials.

Publications

CDK9 degradation Inhibits Gastroesophageal Cancer growth and Overcomes Radiation Resistance by Increasing Chromatin Accessibility and Downregulating YAP1/TEAD signaling.

Zhang YY, Ghelfi M, Xue Y, Chen H, Calendo G, Grana G, Li Y, Athavale D, Balch C, Yao X, Chung W, Wang Z, Spitz F, Tang T, Khazak V, Zhou J, Issa JP, Song S. [Preprint]. 2025 Feb 27:2025.02.22.639565. PMID: 40060472

KAP1 promotes gastric adenocarcinoma progression by activating Hippo/YAP1 signaling via binding to HNRNPAB.

Song S, Fan Y, Zou G, Huo L, Kumar J, Li Y, Wang R, Dai E, Jin J, Scott AW, Shao S, Pizzi MP, Vykoukal JV, Katayama H, Hanash S, Calin GA, Zhang X, Lee MG, Wang Z, Lo YH, Gan Q, Waters RE, Yin F, Wang L, Cheng X, Ajani JA, Dhar SS. Cancer Lett. 2025 Apr 4:217695. doi: 10.1016/j.canlet.2025.217695. Online ahead of print.PMID: 40189014

Exosomal Galectin-3 promotes peritoneal metastases in gastric adenocarcinoma via microenvironment alterations.

Fan Y, Song S, Pizzi MP, Zou G, Vykoukal JV, Yoshimura K, Jin J, Calin GA, Waters RE, Gan Q, Wang L, Hanash S, Dhar SS, Ajani JA. iScience. 2024 Dec 10;28(1):111564. PMID: 39811647

Evolution of Esophageal Adenocarcinoma From Precursor Lesion Stem Cells.

Xian W, Wang S, Xie J, Yamamoto Y, Khorrami M, Zhang Y, Montes RC, Desales C, Khorrami M, Mory Z, Hoffman A, Su A, Nguyen C, Davies PJA, Stephan C, Pan S, Wu W, Liu Y, Siegelman J, Waters RE, Ross WA, Song S, Metersky M, Beer DG, Crum CP, Stewart AJ, Vincent M, Russell R, Izard RA, Ho KY, Hung-Sen Lai J, Bachovchin WW, Ajani JA, McKeon FD. Gastroenterology. 2025 Mar 14:S0016-5085(25)00521-9. PMID: 40090599

HSP90 inhibitor AUY922 suppresses tumor growth and modulates immune response through YAP1-TEAD pathway inhibition in gastric cancer.

Yoshimura K, Zou G, Fan Y, Yamashita K, Wang L, Wu J, Wang R, Shao S, Scott AW, Jin J, Pizzi MP, Yao X, Brown CA, Wang L, Gan Q, Waters RE, Yin F, Song S, Dhar SS, Ajani JA. Cancer Lett. 2025 Feb 1;610:217354. PMID: 39603381

6. SMYD5 methylation of rpL40 links ribosomal output to gastric cancer.

Park J, Wu J, Szkop KJ, Jeong J, Jovanovic P, Husmann D, Flores NM, Francis JW, Chen YC, Benitez AM, Zahn E, Song S, Ajani JA, Wang L, Singh K, Larsson O, Garcia BA, Topisirovic I, Gozani O, Mazur PK. Nature. 2024 Aug;632(8025):656-663. PMID: 39048817 

7. The role of Hippo/YAP1 in cancer-associated fibroblasts: Literature review and future perspectives. Athavale D, Balch C, Zhang Y, Yao X, Song S. Cancer Lett. 2024 Nov 1;604:217244. PMID: 39260668 
8. Tumor-Associated Macrophages as Major Immunosuppressive Cells in the Tumor Microenvironment. Ghebremedhin A, Athavale D, Zhang Y, Yao X, Balch C, Song S. Cancers (Basel). 2024 Oct 8;16(19):3410. PMID: 39410029 
9. Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression.

Wang R, Song S, Qin J, Yoshimura K, Peng F, Chu Y, Li Y, Fan Y, Jin J, Dang M, Dai E, Pei G, Han G, Hao D, Li Y, Chatterjee D, Harada K, Pizzi MP, Scott AW, Tatlonghari G, Yan X, Xu Z, Hu C, Mo S, Shanbhag N, Lu Y, Sewastjanow-Silva M, Fouad Abdelhakeem AA, Peng G, Hanash SM, Calin GA, Yee C, Mazur P, Marsden AN, Futreal A, Wang Z, Cheng X, Ajani JA, Wang L. Cancer Cell. 2023 Aug 14;41(8):1407-1426.e9. PMID: 37419119 

10. Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Chu Y, Dai E, Li Y, Han G, Pei G, Ingram DR, Thakkar K, Qin JJ, Dang M, Le X, Hu C, Deng Q, Sinjab A, Gupta P, Wang R, Hao D, Peng F, Yan X, Liu Y, Song S, Zhang S, Heymach JV, Reuben A, Elamin YY, Pizzi MP, Lu Y, Lazcano R, Hu J, Li M, Curran M, Futreal A, Maitra A, Jazaeri AA, Ajani JA, Swanton C, Cheng XD, Abbas HA, Gillison M, Bhat K, Lazar AJ, Green M, Litchfield K, Kadara H, Yee C, Wang L. Nat Med. 2023 Jun;29(6):1550-1562. PMID: 37248301 
11. Early stage gastric adenocarcinoma: clinical and molecular landscapes.

Hirata Y, Noorani A, Song S, Wang L, Ajani JA. Nat Rev Clin Oncol. 2023 Jul;20(7):453-469. PMID: 37264184 

12. Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment.

Fan Y, Li Y, Yao X, Jin J, Scott A, Liu B, Wang S, Huo L, Wang Y, Wang R, Pool Pizzi M, Ma L, Shao S, Sewastjanow-Silva M, Waters R, Chatterjee D, Liu B, Shanbhag N, Peng G, Calin GA, Mazur PK, Hanash SM, Ishizawa J, Hirata Y, Nagano O, Wang Z, Wang L, Xian W, McKeon F, Ajani JA, Song S. Gut. 2023 Apr;72(4):624-637. PMID: 36002248

13. Galectin-3 Cooperates with CD47 to Suppress Phagocytosis and T-cell Immunity in Gastric Cancer Peritoneal Metastases.

Fan Y, Song S, Li Y, Dhar SS, Jin J, Yoshimura K, Yao X, Wang R, Scott AW, Pizzi MP, Wu J, Ma L, Calin GA, Hanash S, Wang L, Curran M, Ajani JA. Cancer Res. 2023 Nov 15;83(22):3726-3738. PMID: 37738407

14. Clinically conserved genomic subtypes of gastric adenocarcinoma.
15. Jeong YS, Eun YG, Lee SH, Kang SH, Yim SY, Kim EH, Noh JK, Sohn BH, Woo SR, Kong M, Nam DH, Jang HJ, Lee HS, Song S, Oh SC, Lee J, Ajani JA, Lee JS. Mol Cancer. 2023 Sep 6;22(1):147. PMID: 37674200 
16. Challenges and Prospects of Patient-Derived Xenografts for Cancer Research.

Jin J, Yoshimura K, Sewastjanow-Silva M, Song S, Ajani JA. Cancers (Basel). 2023 Aug 31;15(17):4352. PMID: 37686627

17. Proteogenomic landscape of gastric adenocarcinoma peritoneal metastases.

Zhao S, Wang R, Song S, Hao D, Han G, Song X, Zhang J, Pizzi MP, Shanbhag N, Futreal A, Badgwell B, Harada K, Calin G, Vykoukal J, Yu CY, Katayama H, Hanash SM, Wang L, Ajani JA. iScience. 2023 May 19;26(6):106913. PMID: 37305699

18. CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion.

Zou G, Huang Y, Zhang S, Ko KP, Kim B, Zhang J, Venkatesan V, Pizzi MP, Fan Y, Jun S, Niu N, Wang H, Song S, Ajani JA, Park JI. J Exp Med. 2024 Apr 1;221(4):e20230561. doi: 10.1084/jem.20230561.PMID: 36993615

19. A new intronic quantitative PCR method led to the discovery of transformation from human ascites to murine malignancy in a mouse model.

Jin J, Huo L, Fan Y, Wang R, Scott AW, Pizzi MP, Yao X, Shao S, Ma L, Da Silva MS, Yamashita K, Yoshimura K, Zhang B, Wu J, Wang L, Song S, Ajani JA. Front Oncol. 2023 Feb 6;13:1062424. PMID: 36865791 

20. Loss of ARID1A activates mTOR signaling and SOX9 in gastric adenocarcinoma-rationale for targeting ARID1A deficiency.

Dong X, Song S, Li Y, Fan Y, Wang L, Wang R, Huo L, Scott A, Xu Y, Pizzi MP, Ma L, Wang Y, Jin J, Zhao W, Yao X, Johnson RL, Wang L, Wang Z, Peng G, Ajani JA. Gut. 2022 Mar;71(3):467-478. PMID: 33785559

21. GRK3 is a poor prognosticator and serves as a therapeutic target in advanced gastric adenocarcinoma.

Li Y, Fan Y, Xu J, Huo L, Scott AW, Jin J, Yang B, Shao S, Ma L, Wang Y, Yao X, Pool Pizzi M, Sewastjanow Da Silva M, Zhang G, Zhuo L, Cho EJ, Dalby KN, Shanbhag ND, Wang Z, Li W, Song S, Ajani JA. J Exp Clin Cancer Res. 2022 Aug 23;41(1):257. doi: 10.1186/s13046-022-02463-6.PMID: 35996148

22. Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma.

Wang R, Dang M, Harada K, Han G, Wang F, Pool Pizzi M, Zhao M, Tatlonghari G, Zhang S, Hao D, Lu Y, Zhao S, Badgwell BD, Blum Murphy M, Shanbhag N, Estrella JS, Roy-Chowdhuri S, Abdelhakeem AAF, Wang Y, Peng G, Hanash S, Calin GA, Song X, Chu Y, Zhang J, Li M, Chen K, Lazar AJ, Futreal A, Song S, Ajani JA, Wang L. Nat Med. 2021 Jan;27(1):141-151. PMID: 33398161

23. YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition.

Ajani JA, Xu Y, Huo L, Wang R, Li Y, Wang Y, Pizzi MP, Scott A, Harada K, Ma L, Yao X, Jin J, Zhao W, Dong X, Badgwell BD, Shanbhag N, Tatlonghari G, Estrella JS, Roy-Chowdhuri S, Kobayashi M, Vykoukal JV, Hanash SM, Calin GA, Peng G, Lee JS, Johnson RL, Wang Z, Wang L, Song S. Gut. 2021 Jan;70(1):55-66. PMID: 32345613 

24. Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma.

Hao D, He S, Harada K, Pizzi MP, Lu Y, Guan P, Chen L, Wang R, Zhang S, Sewastjanow-Silva M, Abdelhakeem A, Shanbhag N, Bhutani M, Han G, Lee JH, Zhao S, Weston B, Blum Murphy M, Waters R, Estrella JS, Roy-Chowdhuri S, Gan Q, Lee JS, Peng G, Hanash SM, Calin GA, Song X, Zhang J, Song S, Wang L, Ajani JA. Gut. 2021 Nov;70(11):2055-2065. Epub 2020 Dec 17.PMID: 33334899

25. Proteomic profiling of key signatures from gastric lesions to early gastric cancer.

Fan Y, Ajani JA, Song S. EBioMedicine. 2021 Dec;74:103744. PMID: 34902787 

26. Drug resistance and Cancer stem cells.

Li Y, Wang Z, Ajani JA, Song S. Cell Commun Signal. 2021 Feb 15;19(1):19. PMID: 33588867 

27. Patient-derived cell lines and orthotopic mouse model of peritoneal carcinomatosis recapitulate molecular and phenotypic features of human gastric adenocarcinoma. Song S, Xu Y, Huo L, Zhao S, Wang R, Li Y, Scott AW, Pizzi MP, Wang Y, Fan Y, Harada K, Jin J, Ma L, Yao X, Shanbhag ND, Gan Q, Roy-Chowdhuri S, Badgwell BD, Wang Z, Wang L, Ajani JA. J Exp Clin Cancer Res. 2021 Jun 23;40(1):207. PMID: 34162421

Please refer the complete List of Published Work at https://www.ncbi.nlm.nih.gov/myncbi/1votkP-s4I75n/bibliography/public/  

Boopathi Subramaniyan, M.Phil, PhD
Postdoctoral Researcher
Surgical Research Lab, Department of Surgery
Cooper University Health Care
E&R Building, Room 220, 401 Haddon Ave, Camden, NJ 08103
subramaniyan-boopath@cooperhealth.edu

My research interest primarily focuses on NRF2's role in regulating kinases to promote proliferation, metastasis, radio- and chemo-resistance of esophageal squamous cell carcinoma (ESCC). Recently, our lab identified novel kinases downstream of the NRF2 signaling pathway, which may be considered treatment targets. I am also interested in how alcohol drinking contributes to ESCC as a carbon source.

Publications

Yahui Li, Zhaohui Xiong, Chorlada Paiboonrungruang, Boopathi Subramaniyan, Curt Balch, David D. Shersher, Francis Spitz and Xiaoxin Chen. Lymphatic Metastasis of Esophageal Squamous Cell Carcinoma: The Role of NRF2. Cancers [publication details forthcoming].

Qin L, Dong Z, Huang C, Liu H, Beebe J, Subramaniyan B, Hao Y, Liu Y, He Z, Liu JY, Zhang JT. Reversible promoter demethylation of PDGFD confers gemcitabine resistance through STAT3 activation and RRM1 upregulation. Cancer Lett. 2023 Jul 28;567:216266. doi: 10.1016/j.canlet.2023.216266. Epub 2023 Jun 14. PMID: 37321532.

Tilley AMC, Howard CM, Sridharan S, Subramaniyan B, Bearss NR, Alkhalili S, Raman D. The CXCR4-Dependent LASP1-Ago2 Interaction in Triple-Negative Breast Cancer. Cancers (Basel). 2020 Aug 29;12(9):2455. doi: 10.3390/cancers12092455.PMID: 32872485.

Subramaniyan B, Sridharan S, M Howard C, M C Tilley A, Basuroy T, de la Serna I, Butt E, Raman D. Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer. Cancers (Basel). 2020 Aug 21;12(9):2372. doi: 10.3390/cancers12092372.PMID: 32825729.

Sridharan S, Robeson M, Bastihalli-Tukaramrao D, Howard CM, Subramaniyan B, Tilley AMC, Tiwari AK, Raman D. Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness. Front Oncol. 2019 Dec 6;9:1311. doi: 10.3389/fonc.2019.01311. eCollection 2019. PMID: 31867270.

Sridharan S, Howard CM, Tilley AMC, Subramaniyan B, Tiwari AK, Ruch RJ, Raman D. Novel and Alternative Targets Against Breast Cancer Stemness to Combat Chemoresistance. Front Oncol. 2019 Oct 16;9:1003. doi: 10.3389/fonc.2019.01003. eCollection 2019.PMID: 31681564.

For a complete list, click here.

Huan Li, PhD
Research Technician
Surgical Research Division, Department of Surgery
Cooper University Health Care
E&R Building Room 220, 401 Haddon Avenue, Camden, NJ 08103
li-huan@cooperhealth.edu

My research is centered on the field of oncology, encompassing breast cancer, leukemia, colon cancer, and more. My technical expertise lies at the intersection of cell biology, molecular biology, and in vivo experimentation, with a particular emphasis on cancer biology and drug development. I specialize in cell biology, drug resistance screening, chemo-/radio-sensitivity screening, and protein analysis techniques.

Publications

Huan Li, Srinivas Chatla, Xiaolei Liu, Zhen Tian, Umeshkumar Vekariya, Peng Wang, Dongwook Kim, Stacia Octaviani, Zhaorui Lian, George Morton, Zijie Feng, Dan Yang, Katherine Sullivan-Reed, Wayne Childers, Xiang Yu, Kumaraswamy Naidu Chitrala, Jozef Madzo, Tomasz Skorski, Jian Huang. 
ZNF251 haploinsufficiency confers PARP inhibitors resistance in BRCA1-mutated cancer cells through activation of homologous recombination. Cancer Letters, 2025-01-31, Volume 613, 217505. https://doi.org/10.1016/j.canlet.2025.217505

Minjun Xia, Yabim Jiao, Huan Li, Yushan Lin. Comparative Study on Four Phenolic Components of Dashain Refined Chinese Medicine and Common Chinese Medicine. Acta Chinese Medicine and Pharmacology 2017, 451:44-47.

Huan Liming Xia, Yabin Jiao. The protective effect of total glucosides of paeony on rats with atherosclerosis and blood lipid regulation. Jiangxi Journal of Traditional Chinese Medicine 2017; 4:56-58.

Huan Li, Jindong Zhao, Guo sheng Wang. Treatment with Lingzi Capsules Suppresses Colorectal Cancer by Inhibiting the Hepatocyte Growth Factor/c-Met Signal Transduction Pathway. Molecular Medicine Reports 2015; 11: 1865- 1870.

Yahui Li, MS
Research Technician
Surgical Research Division, Department of Surgery
Cooper University Health Care
E&R Building Room 220, 401 Haddon Avenue, Camden, NJ 08103
li-yahui@cooperhealth.edu

My research includes studying the role of NRF2 in the mechanisms of lymphatic metastasis in esophageal squamous cell carcinoma, as well as investigating NRF2's involvement in esophageal carcinogenesis and metastasis through competitive interactions. I have successfully elucidated the mouse esophageal lymphatic drainage system.

Publications

Yahui Li, Zhaohui Xiong, Chorlada Paiboonrungruang, Boopathi Subramaniyan, Curt Balch, David D. Shersher, Francis Spitz and Xiaoxin Chen. Lymphatic Metastasis of Esophageal Squamous Cell Carcinoma: The Role of NRF2. Cancers [publication details forthcoming].

Zena Saleh, Matthew C. Moccia, Zachary Ladd, Upasana Joneja, Yahui Li, Francis Spitz, Young Ki Hong, and Tao Gao. Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation. Int. J. Mol. Sci. 2024, 25, 1331. https://doi.org/10.3390/ijms25021331.

Paiboonrungruang C, Xiong Z, Lamson D, Li Y, Bowman B, Chembo J, Huang C, Li J, Livingston EW, Frank JE, Chen V, Li Y, Weissman B, Yuan H, Williams KP, Major MB, Chen X. Small Molecule Screen Identifies Pyrimethamine as an Inhibitor of NRF2-driven Esophageal Hyperplasia. Redox Biology 2023; 67:102901.

Knapp K, Verchio V, Coburn-Flynn O, Li Y, Xiong Z, Morrison JC, Shersher DD, Spitz F, Chen X. Exploring Cell Competition for the Prevention and Therapy of Esophageal Squamous Cell Carcinoma. Biochemical Pharmacology. 2023; 7:115639.

Li Y, Cheng Q, Xiong Z, Paiboonrungruang C, Adekoya TO, Li Y, Chen X. Lymphatic drainage system and lymphatic metastasis of cancer cell in the mouse esophagus. Digestive Diseases and Sciences. 2023; 68.3: 803-812.

Chen, X, Li, Y, Paiboonrungruang, C, Li, Y, Peters, H, Kist, R, & Xiong, Z. PAX9 in Cancer Development. International Journal of Molecular Sciences. 2022; 23.10: 5589.

Li Y, Li Y, Chen X. Notch and esophageal squamous cell carcinoma. Adv Exp Med Biol. 2021; 1287:59-68.

Adekoya TO, Smith N, Thomas AJ, Lane TS, Burnette N, Rivers EJ, Li Y, Chen X, Richardson RM. Host versus cell-dependent effects of β-arrestin 1 expression in prostate tumorigenesis. Carcinogenesis. 2021; 42:772-83.

Cagle P, Smith N, Adekoya TO, Li Y, Kim S, Rios-Colon L, Deep G, Niture S, Albanese C, Suy S, Collins SP, Kumar D. Knockdown of microRNA-214-3p Promotes Tumor Growth and Epithelial-Mesenchymal Transition in Prostate Cancer. Cancers. 2021; 13:5875.

Paiboonrungruang C, Simpson E, Xiong Z, Huang C, Li J, Li Y, Chen X. Development of targeted therapy of NRF2high esophageal squamous cell carcinoma. Cell Signal. 2021; 86:110105.

Shi M, Ren S, Chen H, Li J, Huang C, Li Y, Han Y, Li Y, Sun Z, Chen X, Xiong Z. Alcohol drinking inhibits NOTCH-PAX9 signaling in esophageal squamous epithelial cells. J Pathol. 2021; 253:384-395.