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Zhu J, Zhou J, Tao C, Xia G, Liu B, Zheng X, Li X, Zhang Z. Identification of early prognostic biomarkers in Severe Fever with Thrombocytopenia Syndrome using machine learning algorithms. Ann Med 2025; 57:2451184. [PMID: 39803909 PMCID: PMC11730770 DOI: 10.1080/07853890.2025.2451184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 12/14/2024] [Accepted: 12/16/2024] [Indexed: 01/16/2025] Open
Abstract
OBJECTIVE We aimed at identifying acute phase biomarkers in Severe Fever with Thrombocytopenia Syndrome (SFTS), and to establish a model to predict mortality outcomes. METHODS A retrospective analysis was conducted on multicenter clinical data. Group-based trajectory modeling (GBTM) was utilized to demonstrate the overall trend of laboratory indicators and their correlation with mortality. Six different machine learning algorithms were employed to develop prognostic models based on the clinical features during the acute phase, which were reduced using Lasso regression. RESULTS Seven indicators (ALT, AST, BUN, LDH, a-HBDH, DD, and PLT) at 7-10 days post-onset and their change slopes were found to be crucial during disease progression. These, along with other clinical features, were reduced to 8 variables using Lasso regression for model construction. The random forest model demonstrated the best performance in both internal validation (AUC: 0.961) and external validation (AUC: 0.948). Decision Curve Analysis indicated a good balance between model benefits and risks. CONCLUSIONS a-HBDH and its change slope along with central nervous symptom manifestations within 7-10 days after onset accurately predicted mortality in SFTS. Various algorithms provided a comprehensive overview of disease progression and constructed more stable and efficient models.
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Affiliation(s)
- Jie Zhu
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jianmei Zhou
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chunhui Tao
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guomei Xia
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Bingyan Liu
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaowei Zheng
- Department of Infectious Diseases, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Xu Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhenhua Zhang
- Institute of Clinical Virology, Department of Infectious Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
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2
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Zhu C, Huang K, Li T, Li Y, Jin Y, Li R, Zhu Z, Yang S, Xia L, Fang B. Manganese dioxide coupled metal-organic framework as mitophagy regulator alleviates periodontitis through SIRT1-FOXO3-BNIP3 signaling axis. Biomaterials 2025; 319:123179. [PMID: 39983516 DOI: 10.1016/j.biomaterials.2025.123179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 01/27/2025] [Accepted: 02/08/2025] [Indexed: 02/23/2025]
Abstract
Periodontitis is a prevalent chronic inflammatory disease characterized by alveolar bone resorption. Its progression is closely linked to oxidative stress where reactive oxygen species (ROS) generated by mitochondria exacerbate inflammation in positive feedback loops. Strategies for mitochondrial regulation hold potential for therapeutic advances. Metal-organic frameworks (MOFs) have shown promise as nanozymes for ROS scavenging. However, inability to directly regulate cellular processes to prevent further ROS production from damaged mitochondria during persistent inflammation makes MOFs insufficient in treating periodontitis. This study synthesizes MnO2@UiO-66(Ce) by introducing MnO2 within nanoscale mesoporous UiO-66 type MOFs. MnO2 coupled with Ce clusters in MOF channels, forms a superoxide dismutase/catalase cascade catalytic system. More importantnly, manganese endows the MOFs with bioactive effects which enhances mitophagy, facilitating the removal of damaged mitochondria, thereby restoring long-term cellular homeostasis. The results demonstrate that this synergistic antioxidant solution MnO2@UiO-66 restores mitochondrial homeostasis and osteogenic activity of periodontal ligament cells in vitro and alleviates inflammatory bone resorption in a ligature-induced periodontitis model in vivo. The SIRT1-FOXO3-BNIP3 signaling axis plays a key role in this process. This study may provide a design strategy that combines a highly efficient cascade catalytic system with long-term regulation of cellular homeostasis to combat oxidative stress in chronic inflammation.
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Affiliation(s)
- Cheng Zhu
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, China
| | - Kai Huang
- Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, 200011, China
| | - Tiancheng Li
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, China
| | - Yixin Li
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, China
| | - Yu Jin
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, China
| | - Ruomei Li
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, China
| | - Zhiyu Zhu
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, China
| | - Shengbing Yang
- Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, 200011, China.
| | - Lunguo Xia
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, China.
| | - Bing Fang
- Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, China.
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3
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Ton Nu QC, Deka G, Park PH. CD8 + T cell-based immunotherapy: Promising frontier in human diseases. Biochem Pharmacol 2025; 237:116909. [PMID: 40179991 DOI: 10.1016/j.bcp.2025.116909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/28/2025] [Accepted: 03/26/2025] [Indexed: 04/05/2025]
Abstract
The abundant cell components of the adaptive immune system called T lymphocytes (T cells) play important roles in mediating immune responses to eliminate the invaders and create the memory of the germs to form a new immunity for the next encounter. Among them, cytotoxic T cells expressing cell-surface CD8 are the most critical effector cells that directly eradicate the target infected cells by recognizing antigens presented by major histocompatibility complex class I molecules to protect our body from pathological threats. In the continuous evolution of immunotherapy, various CD8+ T cell-based therapeutic strategies have been developed based on the role and molecular concept of CD8+ T cells. The emergence of such remarkable therapies provides promising hope for multiple human disease treatments such as autoimmunity, infectious disease, cancer, and other non-infectious diseases. In this review, we aim to discuss the current knowledge on the utilization of CD8+ T cell-based immunotherapy for the treatment of various diseases, the molecular basis involved, and its limitations. Additionally, we summarize the recent advances in the use of CD8+ T cell-based immunotherapy and provide a comprehensive overview of CD8+ T cells, including their structure, underlying mechanism of function, and markers associated with CD8+ T cell exhaustion. Building upon these foundations, we delineate the advancement of CD8+ T cell-based immunotherapies with fundamental operating principles followed by research studies, and challenges, as well as illustrate human diseases involved in this development.
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Affiliation(s)
- Quynh Chau Ton Nu
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Gitima Deka
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Pil-Hoon Park
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea; Research institute of cell culture, Yeungnam University, Gyeongsan, Republic of Korea.
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4
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Klima S, Hurrell T, Goolam M, Gouws C, Engelbrecht AM, Kaur M, van den Bout I. A new dawn: Vitalising translational oncology research in Africa with the help of advanced cell culture models. Transl Oncol 2025; 56:102391. [PMID: 40228390 PMCID: PMC12017847 DOI: 10.1016/j.tranon.2025.102391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 03/12/2025] [Accepted: 04/07/2025] [Indexed: 04/16/2025] Open
Abstract
The advent of in vitro models such as induced pluripotent stem cells (iPSC) and patient derived (disease) organoids is supporting the development of population and patient specific model systems reflecting human physiology and disease. However, there remains a significant underrepresentation of non-European, especially African model systems. The development of such models should be enthusiastically embraced by Sub-Saharan African countries (SSAC) and middle-income countries (LIMC) to direct their own research focused on the improvement of health of their own populations at a sustainable cost within their respective funding environments. Great care needs to be taken to develop national frameworks to direct, sustainably fund and support such efforts in a way that maximises the output of such models for the investment required. Here, we highlight how advanced culture models can play a role in vitalising local healthcare research by focusing on locally relevant health care questions using appropriate cell culture models. We also provide a potential national platform example that could maximise such output at the lowest cost. This framework presents an opportunity for SSAC and LMIC to base their healthcare research on locally relevant models to ensure that developed health care initiatives and interventions are best suited for the populations they serve and thus represent a reset in global health care research at large.
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Affiliation(s)
- Stefanie Klima
- Centre for Neuroendocrinology and Department of Immunology, Faculty of Health Sciences, University of Pretoria, South Africa
| | - Tracey Hurrell
- Bioengineering and Integrated Genomics Group, Council for Scientific and Industrial Research, Pretoria, South Africa; Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, South Africa
| | - Mubeen Goolam
- Department of Human Biology, Faculty of Health Sciences, University of Cape Town, South Africa; UCT Neuroscience Institute, Cape Town, South Africa
| | - Chrisna Gouws
- Centre of Excellence for Pharmaceutical Sciences (Pharmacen™), Faculty of Health Sciences, North-West University, South Africa; Desmond Tutu School of Medicine, Faculty of Health Sciences, North-West University, South Africa
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Mandeep Kaur
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, South Africa
| | - Iman van den Bout
- Department of Physiology, Faculty of Health Sciences, University of Pretoria, South Africa.
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5
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Burtscher J, Motl RW, Berek K, Ehrenreich H, Kopp M, Hohenauer E. Hypoxia in multiple sclerosis. Redox Biol 2025; 83:103666. [PMID: 40347693 DOI: 10.1016/j.redox.2025.103666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2025] [Revised: 05/05/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025] Open
Abstract
Low oxygen availability (hypoxia) is a prominent but poorly understood feature in multiple sclerosis (MS). Whether hypoxia causes or drives MS pathology and symptoms or whether it is a consequence of other pathological events, such as inflammation and vascular dysfunction, is unknown. Here, we summarize the available literature on the interplay between hypoxia and both pathological and symptomatic features of MS. Severe environmental hypoxia (i.e., altitude) may trigger or facilitate MS-related events, possibly by exacerbating tissue hypoxia in the central nervous system. Accordingly, increasing oxygen supply can mitigate pathological and clinical parameters in MS models. In contrast, stimulating the endogenous hypoxia response and adaptation systems by controlled exposure to hypoxia (hypoxia conditioning) renders the central nervous system more resistant to hypoxic insults, thereby attenuating pathology and symptomatology in MS models. Overlapping mechanisms likely play a role in the benefits conferred by physical activity in MS. We provide an integrative model to explain the paradoxically beneficial outcomes of both increased and decreased ambient oxygen conditions. In conclusion, controlled exposure to hypoxia, perhaps in combination with exercise, is a promising, possibly disease-course modifying therapeutic approach for MS. However, many open questions remain.
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Affiliation(s)
- Johannes Burtscher
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria.
| | - Robert W Motl
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL, USA
| | - Klaus Berek
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Hannelore Ehrenreich
- Experimental Medicine, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J 5, Mannheim, Germany
| | - Martin Kopp
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria
| | - Erich Hohenauer
- Rehabilitation and Exercise Science Laboratory, Department of Business Economics, Health and Social Care, University of Applied Sciences and Arts of Southern Switzerland, Landquart, Switzerland; Department of Neurosciences and Movement Science, University of Fribourg, Fribourg, Switzerland
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6
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Smith KWY, Fung SL, Wu HF, Chiesa I, Vozzi G, De Maria C, Gottardi R. Developing an in vitro osteochondral micro-physiological system for modeling cartilage-bone crosstalk in arthritis. Front Immunol 2025; 16:1495613. [PMID: 40491903 PMCID: PMC12146386 DOI: 10.3389/fimmu.2025.1495613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 04/10/2025] [Indexed: 06/11/2025] Open
Abstract
Introduction Arthritis, a disease affecting over 50 million adults in the United States, encompasses many different conditions involving joints and surrounding tissues. Disease development, progression, and subsequent treatment is dependent on many different factors, including the relationship between adjacent tissues and the immunological signals involved. A major contributor to disease regulation is the crosstalk between the cartilage and the bone in joints, as well as their reaction to immune factors such as cytokine signaling and macrophage mediation. Studying cartilage-bone crosstalk in arthritis development can be difficult, as controlling immunological factors in vivo is challenging, but in vitro models often lack multi-tissue relevancy. Methods To fix this, we developed an in vitro micro-physiological system using a biphasic bioreactor that supports modeling of multiple tissues. We generated cartilage and vascularized-bone analogs and combined them in the bioreactor to allow diffusion and signaling between them. Using this system, we directly induced inflammation in the cartilage region and studied how crosstalk between the two adjacent tissues contributed to disease progression. Results We showed that conditioned media from pro-inflammatory macrophages generated a different inflammatory profile than a simple inflammatory cytokine cocktail. We also showed that the vascularized-bone region became inflamed in response to the cartilage inflammation, verifying crosstalk in the system and successfully modeling the relationship between cartilage and bone in an arthritic environment. Discussion This model can be used to further probe the crosstalk between bone and cartilage in arthritis, allowing researchers to tease out the effect of specific inflammatory agents or therapeutics in vitro.
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Affiliation(s)
- Kyra W. Y. Smith
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, United States
- Pulmonary and Sleep Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Stephanie L. Fung
- Pulmonary and Sleep Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Hsin-Fang Wu
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, United States
- Pulmonary and Sleep Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Irene Chiesa
- Pulmonary and Sleep Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Information Engineering and Research Center E. Piaggio, University of Pisa, Pisa, Italy
| | - Giovanni Vozzi
- Department of Information Engineering and Research Center E. Piaggio, University of Pisa, Pisa, Italy
| | - Carmelo De Maria
- Department of Information Engineering and Research Center E. Piaggio, University of Pisa, Pisa, Italy
| | - Riccardo Gottardi
- Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, United States
- Pulmonary and Sleep Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Division of Otolaryngology, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Otorhinolaryngology, Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Orthopaedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
- Ri.MED Foundation, Palermo, PA, Italy
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7
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Sengupta A, Schmid S, Grangier N, Dorn A, Hebestreit M, Hugi A, Žajdlíková K, Herbst A, Losada-Oliva P, Ortolf-Wahl H, Krebs P, Stucki JD, van der Velpen V, Perez-Gil J, Krebs T, Hobi N, Guenat OT. A next-generation system for smoke inhalation integrated with a breathing lung-on-chip to model human lung responses to cigarette exposure. Sci Rep 2025; 15:18181. [PMID: 40414911 DOI: 10.1038/s41598-025-00438-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 04/28/2025] [Indexed: 05/27/2025] Open
Abstract
Continuous exposure to cigarette smoke (CS) significantly contributes to the development and progression of chronic obstructive pulmonary disease (COPD) and lung cancer. Animal models that inhale smoke nasally and have different lung physiology from humans may not accurately replicate cigarette smoke-induced health effects. Furthermore, traditional in vitro models fail to replicate the lung's dynamic mechanical forces and realistic inhalation exposure patterns, limiting their relevance in preclinical research. Here, we introduce an advanced smoke inhalation-based lung-on-chip system, the Continuous Flow AX12 (CFAX12), to investigate CS-induced cellular responses in a physiologically relevant manner. Unlike previous technologies, the CFAX12 integrates cyclic mechanical stretch with controlled whole-smoke exposure, allowing for a more accurate recreation of CS-induced alveolar microenvironment dynamics and barrier integrity responses. Using human alveolar epithelial cells, lung microvascular endothelial cells, and macrophages in mono- and co-culture models under air-liquid interface (ALI) conditions with breathing-like stretch (Str), we simulated key lung microenvironment features. Our results show that CS exposure using the CFAX12 induced a ~ 60% reduction in trans-barrier electrical resistance (TER), increased ROS generation depending on cellular model complexity, and a ~ 4.5-fold increase in IL-8 gene expression, all key hallmarks of early COPD pathogenesis. These findings underscore smoke-induced epithelial damage, inflammation, and oxidative stress, all of which contribute to alveolar barrier dysfunction and disease progression. Also, CFAX12 provides a more physiologically relevant alternative to submerged cigarette smoke extract (CSE) treatments, offering controlled whole-smoke exposure using the VC10 Smoking Robot, ensuring precisely regulated smoke delivery. Additionally, inclusion of pulmonary surfactant reduced IL8 gene levels by ~ 5 folds. Hence, by integrating mechanical and biological complexity, CFAX12 offers a robust platform for assessing inhaled smoke effects and identifying therapeutic targets. It's application in COPD drug screening can facilitate the discovery of compounds that preserve alveolar integrity, reduce inflammation, and mitigate oxidative damage, ultimately bridging the gap between regulatory and preclinical research applications.
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Affiliation(s)
- Arunima Sengupta
- Organs-On-Chip Technologies, ARTORG Center for Biomedical Engineering, University of Bern, Bern, Switzerland.
- Alexis Technologies AG, Bern, Switzerland.
| | - Saskia Schmid
- Organs-On-Chip Technologies, ARTORG Center for Biomedical Engineering, University of Bern, Bern, Switzerland
- Alexis Technologies AG, Bern, Switzerland
| | | | - Aurélien Dorn
- Organs-On-Chip Technologies, ARTORG Center for Biomedical Engineering, University of Bern, Bern, Switzerland
- Alexis Technologies AG, Bern, Switzerland
| | | | - Andreas Hugi
- Swiss Organs-On-Chip Innovation, AlveoliX AG, Bern, Switzerland
| | - Kristína Žajdlíková
- Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Anja Herbst
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Paula Losada-Oliva
- Department of Biochemistry, Faculty of Biology, and Research Institute "Hospital 12 de Octubre (i+12)", Universidad Complutense, Madrid, Spain
| | | | - Philippe Krebs
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Janick D Stucki
- Swiss Organs-On-Chip Innovation, AlveoliX AG, Bern, Switzerland
| | - Vera van der Velpen
- Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Jesus Perez-Gil
- Department of Biochemistry, Faculty of Biology, and Research Institute "Hospital 12 de Octubre (i+12)", Universidad Complutense, Madrid, Spain
| | | | - Nina Hobi
- Swiss Organs-On-Chip Innovation, AlveoliX AG, Bern, Switzerland
| | - Olivier T Guenat
- Organs-On-Chip Technologies, ARTORG Center for Biomedical Engineering, University of Bern, Bern, Switzerland.
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8
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Hans A, Salil, Sawant P, Ajgaonkar B, Jain R, Dandekar P. Cryopreservation of human lung adenocarcinoma spheroids using MMC based cryomixtures. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2025:1-22. [PMID: 40372794 DOI: 10.1080/09205063.2025.2502096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/04/2025] [Indexed: 05/17/2025]
Abstract
Cryopreservation remains crucial bottleneck for storing and transporting bioengineered 3D cell models, vital for preclinical drug development and cancer research. Conventional cryoprotectants like fetal bovine serum (FBS) and dimethyl sulfoxide (DMSO) present cytotoxicity challenges and lack efficacy in maintaining structural integrity and viability in complex 3D culture models. This study investigates the efficacy of two carbohydrate-based macromolecular crowders (MMCs), polydextrose III (PD) and resistant maltodextrin (rMD), in cryopreserving human lung adenocarcinoma spheroids as alternatives to FBS. Spheroids were cryopreserved at -80 and -196 °C using MMC-based cryomixtures, with subsequent evaluation of cell viability, structural integrity, and proliferation markers post-thaw. Results indicate that MMC-based cryomixtures, particularly PD, provide superior cryoprotection, preserving the structural and functional integrity of A549 spheroids over a 60-day storage period at -196 °C. Immunocytochemistry of vimentin and Ki67 biomarkers demonstrated that PD-cryopreserved spheroids exhibited consistent structural stability and retained proliferative capacity, contrasting with those stored in conventional FBS-based cryomixtures, which showed marked deterioration in cellular morphology and viability. Apoptosis profiling revealed a lower incidence of cell death in MMC-preserved spheroids, with live cell percentages stabilizing around 50% at -80 °C and approximately 54% at -196 °C over the extended storage period. Further characterization revealed protection of the necrotic core and cellular junctions PD-cryopreserved spheroids. These findings suggest that MMC-based cryomixtures, especially PD, are effective alternatives for cryopreservation of tumor spheroids. The increased cellular viability and structural preservation provided by MMCs could advance their application in 3D culture preservation, addressing limitations of conventional cryopreservation in drug testing, regenerative medicine, and cancer research.
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Affiliation(s)
- Aakarsh Hans
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
| | - Salil
- Department of Biological Sciences and Biotechnology, Institute of Chemical Technology, Mumbai, India
| | - Pooja Sawant
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
| | - Bhargavi Ajgaonkar
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
| | - Ratnesh Jain
- Department of Biological Sciences and Biotechnology, Institute of Chemical Technology, Mumbai, India
| | - Prajakta Dandekar
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India
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9
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Zhang X, Zhao M, Deng P, Liu H, Li H, Zhang X, Wang D, Qin J. Modeling Idiopathic Inflammatory Myopathy in the Bioinspired Muscle Tissue on Chip. Adv Healthc Mater 2025:e2405111. [PMID: 40357815 DOI: 10.1002/adhm.202405111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 04/21/2025] [Indexed: 05/15/2025]
Abstract
Idiopathic inflammatory myopathy (IIM) is an autoimmune disease that characterized by non-purulent inflammation of the skeletal muscle. However, due to the limitation of study model that can recapitulate the complex pathological process of IIM, the pathogenesis of IIM is still not fully clear. This manuscript develops a vascularized muscle tissue model on a chip that allows to model the immunity mediated pathological changes in IIM. This vascularized muscle model is constructed by layer-by-layer assembly, which could coculture of endothelial cells, myoblasts, and monocytes in a perfusable 3D system. The vascularized muscle model exhibits good biofunctions, including muscle cells alignment and fusion, myofibers generation, force production and expression of muscular biomarkers (myosin heavy chains 1, myosin heavy chains 7, actinin alpha 2, myogenin, and Desmin). Exposure to perfusion of activated monocytes, this work observes the functional changes of muscle tissue, which referred to myofibers atrophy, inflammatory response, and downregulated expression of muscle mature marker, consistent with clinical features of IIM. This work provides a unique platform for modelling IIM and paves a promising avenue for myopathies study and drug testing.
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Affiliation(s)
- Xu Zhang
- Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
| | - Mengqian Zhao
- Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Pengwei Deng
- University of Science and Technology of China, Hefei, 230026, China
- Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou, 215123, China
| | - Haitao Liu
- Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
| | - Hongjing Li
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Xiaoqing Zhang
- Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
| | - Daqing Wang
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Jianhua Qin
- Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- University of Science and Technology of China, Hefei, 230026, China
- Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou, 215123, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Chinese Academy of Sciences, Beijing, 100101, China
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10
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Noga M, Jurowski K. Reexamining the acute toxicity of chloropicrin: Comprehensive estimation using in silico methods. Toxicol In Vitro 2025; 105:106033. [PMID: 40020763 DOI: 10.1016/j.tiv.2025.106033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 01/27/2025] [Accepted: 02/15/2025] [Indexed: 03/03/2025]
Abstract
Chloropicrin, historically infamous as a chemical warfare agent during World War I, has recently resurfaced in global conflicts, prompting a reevaluation of its acute toxicological significance. This study addresses the historical knowledge gap surrounding chloropicrin by employing in silico toxicology methods to estimate toxicophores and predict acute toxicity across various exposure routes. Allegations of its use in recent conflicts necessitate a deeper understanding of its toxicological profile, particularly in modern warfare scenarios. Qualitative analysis (STopTox and admetSAR) revealed chloropicrin to be toxic for oral, dermal, and inhalation administration, with the nitro group attached to the carbon atom identified as a significant contributor to its toxic profile. Quantitative in silico estimates, using multiple methods (TEST, ProTox-II, ADMETlab, ACD/Labs Percepta and QSAR Toolbox), indicated t-LD50 values of 48.71 mg/kg bw for oral exposure, 130.16 mg/kg bw for dermal exposure, and an inhalation t-LC50 of 0.022 mg/L. However, method inconsistencies and variability in dose conversion guidance highlight the importance of a cautious approach to interpreting results. Furthermore, the study explores the potential of in silico methods to reduce reliance on animal testing, providing a more efficient and humane alternative for toxicity assessments. The findings contribute to a comprehensive understanding of chloropicrin's acute toxicity, emphasising the relevance of in silico methods in guiding future toxicological studies and informing safety assessments in agricultural and wartime scenarios.
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Affiliation(s)
- Maciej Noga
- Department of Regulatory and Forensic Toxicology, Institute of Medical Expertises in Łódź, ul. Aleksandrowska 67/93, 91-205 Łódź, Poland
| | - Kamil Jurowski
- Department of Regulatory and Forensic Toxicology, Institute of Medical Expertises in Łódź, ul. Aleksandrowska 67/93, 91-205 Łódź, Poland; Laboratory of Innovative Toxicological Research and Analyzes, Institute of Medical Studies, Medical College, Rzeszów University, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland.
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11
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Keramati F, Leijte GP, Bruse N, Grondman I, Habibi E, Ruiz-Moreno C, Megchelenbrink W, Peters van Ton AM, Heesakkers H, Bremmers ME, van Grinsven E, Tesselaar K, van Staveren S, van der Velden WJ, Preijers FW, Te Pas B, van de Loop R, Gerretsen J, Netea MG, Stunnenberg HG, Pickkers P, Kox M. Systemic inflammation impairs myelopoiesis and interferon type I responses in humans. Nat Immunol 2025; 26:737-747. [PMID: 40251340 PMCID: PMC12043512 DOI: 10.1038/s41590-025-02136-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 03/17/2025] [Indexed: 04/20/2025]
Abstract
Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory CD163+SLC39A8+CALR+ monocyte-like subset (infMono) at 4 h post-LPS administration. The late immunosuppressive phase was characterized by diminished expression of type I interferon (IFN)-responsive genes in monocytes, impaired myelopoiesis and a pronounced attenuation of the immune response on a secondary LPS challenge 1 week after the first. The infMono gene program and impaired myelopoiesis were also detected in patient cohorts with bacterial sepsis and coronavirus disease. IFNβ treatment restored type-I IFN responses and proinflammatory cytokine production and induced monocyte maturation, suggesting a potential treatment option for immunosuppression.
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Affiliation(s)
- Farid Keramati
- Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, The Netherlands
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Guus P Leijte
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Niklas Bruse
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Inge Grondman
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ehsan Habibi
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Québec, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Québec, Canada
| | - Cristian Ruiz-Moreno
- Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, The Netherlands
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Wout Megchelenbrink
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | | | - Hidde Heesakkers
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Manita E Bremmers
- Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Erinke van Grinsven
- Department of Respiratory Medicine and Center of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Kiki Tesselaar
- Department of Respiratory Medicine and Center of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Selma van Staveren
- Department of Respiratory Medicine and Center of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- TmonoCOAST, Amsterdam, The Netherlands
| | | | - Frank W Preijers
- Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Brigit Te Pas
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Raoul van de Loop
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jelle Gerretsen
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mihai G Netea
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania
| | - Hendrik G Stunnenberg
- Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, The Netherlands.
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
| | - Peter Pickkers
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Matthijs Kox
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
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12
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Qualls KA, Kadakia FK, Serafin EK, Lückemeyer DDN, Davidson S, Strong JA, Zhang JM. mRNA Expression of Mineralocorticoid and Glucocorticoid Receptors in Human and Mouse Sensory Neurons of the Dorsal Root Ganglia. Anesth Analg 2025; 140:1216-1226. [PMID: 39808573 PMCID: PMC11919799 DOI: 10.1213/ane.0000000000007133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
BACKGROUND Corticosteroid receptors, including mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), play important roles in inflammatory pain in the dorsal root ganglion (DRG). Although it is widely known that activating the GR reduces inflammatory pain, it has recently been shown that MR activation contributes to pain and neuronal excitability in rodent studies. Moreover, little is known about the translation of this work to humans, or the mechanisms through which corticosteroid receptors regulate inflammatory pain. METHODS Corticosteroid receptor expression in human and mouse DRGs was characterized. RNAscope was used to perform high-resolution in situ hybridization for GR and MR mRNAs and to examine their colocalization with markers for nociceptors ( SCN10A , Na V 1.8 mRNA) and Aβ mechanoreceptors ( KCNS1 , Kv9.1 mRNA) in human DRG and C57BL/6J mouse DRG samples. RESULTS GR and MR mRNAs are expressed in almost all DRG neurons across species. The 2 receptors colocalize in 99.2% of human DRG neurons and 95.9% of mouse DRG neurons ( P = .0004, Fisher exact test). In both human and mouse DRGs, the large-diameter KCNS1+ Aβ mechanoreceptors showed a significantly higher MR/GR ratio (MR-leaning) compared to KCNS1- neurons (human: 0.23 vs 0.04, P = .0002; mouse: 0.35 vs -0.24, P < .0001; log ratios, unpaired t test), whereas small-diameter SCN10A+ nociceptive neurons showed a significantly lower MR/GR ratio (GR-leaning) compared to SCN10A- neurons (human: -0.02 vs 0.18, P = .0001; mouse: -0.16 vs 0.08, P < .0001; log ratios, unpaired t test). CONCLUSIONS These findings indicate that mouse corticosteroid receptor mRNA expression reflects human expression in the DRG, and that mice could be a suitable model for studying corticosteroid receptor involvement in pain. Additionally, this study supports the translatability of rodent data to humans for the use of more selective corticosteroids at the DRG in pain treatments.
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MESH Headings
- Ganglia, Spinal/metabolism
- Animals
- Receptors, Mineralocorticoid/genetics
- Receptors, Mineralocorticoid/biosynthesis
- Receptors, Mineralocorticoid/metabolism
- Humans
- Receptors, Glucocorticoid/genetics
- Receptors, Glucocorticoid/biosynthesis
- Receptors, Glucocorticoid/metabolism
- Mice, Inbred C57BL
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Messenger/biosynthesis
- Sensory Receptor Cells/metabolism
- Male
- Mice
- Female
- Middle Aged
- Species Specificity
- Nociceptors/metabolism
- Adult
- NAV1.8 Voltage-Gated Sodium Channel/genetics
- NAV1.8 Voltage-Gated Sodium Channel/metabolism
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Affiliation(s)
- Katherine A Qualls
- From the Department of Anesthesiology, Pain Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
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13
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Levinson S, Pulli B, Heit JJ. Neuroinflammation and acute ischemic stroke: impact on translational research and clinical care. Front Surg 2025; 12:1501359. [PMID: 40356948 PMCID: PMC12066521 DOI: 10.3389/fsurg.2025.1501359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 04/07/2025] [Indexed: 05/15/2025] Open
Abstract
Background Stroke, encompassing both ischemic and hemorrhagic subtypes, is a leading cause of mortality and disability globally and current treatments remain limited. Neuroinflammation plays a crucial role in the pathophysiology of stroke, influencing both acute injury and long-term recovery. Objective This review aims to provide a comprehensive overview of neuroinflammation in stroke, detailing the mechanisms, clinical implications, and potential therapeutic strategies. Methods A detailed literature review was conducted, focusing on recent advancements in understanding the neuroinflammatory processes in stroke, including the roles of thromboinflammation, blood-brain barrier (BBB) disruption, and the immune response. Results The initial ischemic insult triggers an inflammatory cascade involving both innate and adaptive immune responses. BBB disruption allows peripheral immune cells and neurotoxic substances to infiltrate the brain, exacerbating neuronal damage and increasing the risk of infections such as pneumonia and urinary tract infections. Thromboinflammation, characterized by platelet activation and immune cell interactions, further complicates the ischemic environment. Proteomic studies have identified key biomarkers that offer insights into neuroinflammatory mechanisms and potential therapeutic targets. Advances in imaging techniques, such as PET and MRI, enable real-time monitoring of neuroinflammation, facilitating personalized treatment approaches. Conclusion Neuroinflammation significantly impacts stroke outcomes, presenting both challenges and opportunities for treatment. Current immunologic therapeutic strategies are limited. Future research should aim to further elucidate the complex immune interactions in stroke, refine imaging biomarkers for clinical use, and develop effective interventions to mitigate neuroinflammation.
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Affiliation(s)
- Simon Levinson
- Department of Neurosurgery, School of Medicine, Stanford University, Stanford, CA, United States
| | - Benjamin Pulli
- Department of Radiology, School of Medicine, Stanford University, Stanford, CA, United States
| | - Jeremy J. Heit
- Department of Radiology, School of Medicine, Stanford University, Stanford, CA, United States
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14
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Jeong PS, Yang HJ, Park YH, Jin YB, Song BS, Hong JJ, Lee SH, Lee JH, Lim KS, Jeong KJ, Kang P, Lee HY, Son HC, Kim HN, Ha SM, Hwang EH, Cha JJ, Jung Y, Choi SA, Lee S, Lee SR, Lee SC, Kang KS, Hur CG, Jung YW, Koo DB, Choo YK, Kim JM, Sim BW, Kim SU. JAK3-deficient mini-pigs exhibit impaired lymphoid organogenesis, intestinal structure, and leukocyte/cytokine production. J Adv Res 2025:S2090-1232(25)00280-2. [PMID: 40280544 DOI: 10.1016/j.jare.2025.04.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 01/09/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025] Open
Abstract
INTRODUCTION Severe combined immunodeficiency (SCID) mini-pigs are a highly versatile model for human disease research and regenerative medicine. OBJECTIVES This study aims to generate a novel JAK3-deficient mini-pig model with a human-like immune system and to elucidate how JAK3 plays an important role in immune system. METHODS JAK3 and RAG2 knockout (KO) mini-pigs were generated using CRISPR/Cas9 and somatic cell nuclear transfer. These mini-pigs were transferred to a sterilized isolator within a specific pathogen-free facility. Phenotypic characteristics and clinical manifestations were analyzed through histological and hematological analysis of SCID mini-pigs to explore the unique role of JAK3 in immune functions. RESULTS JAK3 KO was characterized by defects in T and NK cells, very low levels of B cells, and a complete absence of thymus and lymph nodes. Notably, JAK3 KO mini-pigs had significantly reduced numbers of monocytes in peripheral blood, macrophages in tissue, and inflammatory cytokines, suggesting that JAK3 KO can induce a broad immunodeficiency that extends to the myeloid system as well as the lymphoid. Moreover, JAK3 KO mini-pigs had intestinal abnormalities similar to those of patients. CONCLUSION These results suggest that JAK3 KO mini-pigs can be used as an effective model for the development of therapies for SCID patients, as well as for regenerative medicine applications such as the development of patient-specific artificial organs.
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Affiliation(s)
- Pil-Soo Jeong
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Biotechnology, Daegu University, Gyeongsan, Republic of Korea
| | - Hae-Jun Yang
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Biological Science, College of National Sciences, Wonkwang University, Iksan, Republic of Korea
| | - Young-Ho Park
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Yeung Bae Jin
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Bong-Seok Song
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Jung Joo Hong
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Seung Hwan Lee
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Jong-Hee Lee
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kyung Seob Lim
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Kang-Jin Jeong
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Philyong Kang
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Hwal-Yong Lee
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Hee-Chang Son
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Han-Na Kim
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Seung-Min Ha
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Eun-Ha Hwang
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Jae-Jin Cha
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea
| | - Yena Jung
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Research Institute, huMetaCELL Inc., Bucheon, Republic of Korea
| | - Seon-A Choi
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Companion Animals, Chungcheong University, Cheongju, Republic of Korea
| | - Sanghoon Lee
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Sang-Rae Lee
- Department of Pharmacology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Seung-Chan Lee
- Bio Division, APURES Inc., Pyeongtaek, Republic of Korea
| | - Kyung Soo Kang
- Bio Division, APURES Inc., Pyeongtaek, Republic of Korea; Department of Bio Life Sciences, Shingu College, Seongnam, Republic of Korea
| | - Chang-Gi Hur
- Bio Division, APURES Inc., Pyeongtaek, Republic of Korea
| | - Yong Woo Jung
- College of Pharmacy, Korea University, Sejong, Republic of Korea
| | - Deog-Bon Koo
- Department of Biotechnology, Daegu University, Gyeongsan, Republic of Korea
| | - Young-Kug Choo
- Department of Biological Science, College of National Sciences, Wonkwang University, Iksan, Republic of Korea
| | - Jin-Man Kim
- Department of Pathology, Cancer Research Institute and Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Bo-Woong Sim
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea.
| | - Sun-Uk Kim
- Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea.
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15
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Sharif E, Mobasheri T, Mohit E. Bioengineered ClearColi™-derived outer membrane vesicles displaying CT26 neoepitopes as potent vaccine adjuvants against colon carcinoma in a preventive mouse model. Vaccine 2025; 53:127088. [PMID: 40209628 DOI: 10.1016/j.vaccine.2025.127088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 03/17/2025] [Accepted: 03/29/2025] [Indexed: 04/12/2025]
Abstract
The mutation frequency of colorectal cancer, the third most diagnosed tumor worldwide, is usually very high. To simultaneously target several mutations, we previously designed a CT26 polytope containing neoepitopes and epitopes of the murine CT26 colon cancer cell line. Additionally, to overcome the low immunogenicity of the CT26 polytope vaccine, we isolated recombinant outer membrane vesicles (rOMVs) displaying CT26 polytope from ClearColi™ and found that they induce antitumor immunity. In light of our previous studies, in this study, the recombinant CT26 polytope was chosen as the antigen to investigate the role of ClearColi™-derived OMVs and rOMVs displaying the CT26 polytope as adjuvants against colorectal carcinoma. CT26 polytope vaccine alone and in combination with OMV, rOMV displaying CT26 polytope, and alum as adjuvants were administered to BALB/c mice. Then, the humoral immunity specific to CT26-M90 and CT26 polytope and the stimulated IFN-γ, TNF-α, IL-10, and granzyme B were evaluated. Furthermore, the preventive effect of different immunization strategies against CT26 cells was assessed. Herein, immunization with OMVs and, particularly, rOMVs as adjuvants in combination with CT26 polytope resulted in higher production of CT26 polytope- and CT26-M90 peptide-specific IgG2a antibodies, an indicator of potential Th1 response, and enhanced levels of IFN-γ and TNF-α compared to alum. Furthermore, rOMVs as adjuvants induced higher levels of granzyme B and protection against CT26 characterized by significant reduction of tumor size compared to alum as adjuvants. This study indicates the efficacy of rOMVs and OMVs as adjuvants in combination with the CT26 polytope in a preventive CT26 mouse model. rOMVs delivering polytopic antigens, including different neoepitopes and epitopes as adjuvants, can provide promising platforms for the development of personalized cancer vaccines and vaccines against diseases containing highly variable antigens.
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Affiliation(s)
- Elham Sharif
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Pharmacognosy & Pharmaceutical Biotechnology, School of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Taranom Mobasheri
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Tehran, Iran
| | - Elham Mohit
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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16
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Wang H, Ayala A, Aziz M, Billiar TR, Deutschman CS, Jeyaseelan S, Tang D, Wang P. Value of animal sepsis research in navigating the translational labyrinth. Front Immunol 2025; 16:1593342. [PMID: 40303397 PMCID: PMC12037402 DOI: 10.3389/fimmu.2025.1593342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Accepted: 04/04/2025] [Indexed: 05/02/2025] Open
Affiliation(s)
- Haichao Wang
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Alfred Ayala
- Division of Surgical Research, Brown University Health-Rhode Island Hospital, Providence, RI, United States
- Department of Surgery, the Warren Alpert School of Medicine at Brown University, Providence, RI, United States
| | - Monowar Aziz
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Timothy R. Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Clifford S. Deutschman
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Samithamby Jeyaseelan
- Department of Pathobiological Science, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States
| | - Ping Wang
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
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17
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Brunmaier LAE, Ozdemir T, Walker TW. Angiogenesis: Biological Mechanisms and In Vitro Models. Ann Biomed Eng 2025:10.1007/s10439-025-03721-2. [PMID: 40210793 DOI: 10.1007/s10439-025-03721-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 03/25/2025] [Indexed: 04/12/2025]
Abstract
The translation of biomedical devices and drug research is an expensive and long process with a low probability of receiving FDA approval. Developing physiologically relevant in vitro models with human cells offers a solution to not only improving the odds of FDA approval but also to expand our ability to study complex in vivo systems in a simpler fashion. Animal models remain the standard for pre-clinical testing; however, the data from animal models is an unreliable extrapolation when anticipating a human response in clinical trials, thus contributing to the low rates of translation. In this review, we focus on in vitro vascular or angiogenic models because of the incremental role that the vascular system plays in the translation of biomedical research. The first section of this review discusses the most common angiogenic cytokines that are used in vitro to initiate angiogenesis, followed by angiogenic inhibitors where both initiators and inhibitors work to maintain vascular homeostasis. Next, we evaluate previously published in vitro models, where we evaluate capturing the physical environment for biomimetic in vitro modeling. These topics provide a foundation of parameters that must be considered to improve and achieve vascular biomimicry. Finally, we summarize these topics to suggest a path forward with the goal of engineering human in vitro models that emulate the in vivo environment and provide a platform for biomedical device and drug screening that produces data to support clinical translation.
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Affiliation(s)
- Laura A E Brunmaier
- Nanoscience and Biomedical Engineering Department, South Dakota School of Mines & Technology, 501 E St. Joseph St., Rapid City, SD, 57701, USA
| | - Tugba Ozdemir
- Nanoscience and Biomedical Engineering Department, South Dakota School of Mines & Technology, 501 E St. Joseph St., Rapid City, SD, 57701, USA
| | - Travis W Walker
- Karen M. Swindler Department of Chemical and Biological Engineering, South Dakota School of Mines & Technology, 501 E St. Joseph St., Rapid City, SD, 57701, USA.
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18
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Kim SY, van de Wetering M, Clevers H, Sanders K. The future of tumor organoids in precision therapy. Trends Cancer 2025:S2405-8033(25)00073-1. [PMID: 40185656 DOI: 10.1016/j.trecan.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 03/07/2025] [Accepted: 03/10/2025] [Indexed: 04/07/2025]
Abstract
Tumoroids are cultures of patient-derived tumor cells, which are grown in 3D in the presence of an extracellular matrix extract and specific growth factors. Tumoroids can be generated from adult as well as pediatric cancers, including epithelial cancers, sarcomas, and brain cancers. Tumoroids retain multi-omic characteristics of their corresponding tumor and recapitulate interpatient and intratumor heterogeneity. Retrospective and prospective studies have demonstrated that tumoroids predict patient responses to anticancer therapies, making them a promising tool for precision oncology. However, several challenges remain before tumoroids can be fully integrated into clinical decision-making, including success rates of tumoroid establishment and turnaround times. This review discusses the current advances, challenges, and future directions of tumoroid-based models in cancer research and precision therapy.
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Affiliation(s)
- Seok-Young Kim
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | | | - Hans Clevers
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, The Netherlands; Current address: Roche Pharmaceutical Research and Early Development (pRED) of F. Hoffmann-La Roche Ltd, Basel, Switzerland.
| | - Karin Sanders
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
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19
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Shamul JG, Wang Z, Gong H, Ou W, White AM, Moniz-Garcia DP, Gu S, Clyne AM, Quiñones-Hinojosa A, He X. Meta-analysis of the make-up and properties of in vitro models of the healthy and diseased blood-brain barrier. Nat Biomed Eng 2025; 9:566-598. [PMID: 39304761 PMCID: PMC11922799 DOI: 10.1038/s41551-024-01250-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/08/2024] [Indexed: 09/22/2024]
Abstract
In vitro models of the human blood-brain barrier (BBB) are increasingly used to develop therapeutics that can cross the BBB for treating diseases of the central nervous system. Here we report a meta-analysis of the make-up and properties of transwell and microfluidic models of the healthy BBB and of BBBs in glioblastoma, Alzheimer's disease, Parkinson's disease and inflammatory diseases. We found that the type of model, the culture method (static or dynamic), the cell types and cell ratios, and the biomaterials employed as extracellular matrix are all crucial to recapitulate the low permeability and high expression of tight-junction proteins of the BBB, and to obtain high trans-endothelial electrical resistance. Specifically, for models of the healthy BBB, the inclusion of endothelial cells and pericytes as well as physiological shear stresses (~10-20 dyne cm-2) are necessary, and when astrocytes are added, astrocytes or pericytes should outnumber endothelial cells. We expect this meta-analysis to facilitate the design of increasingly physiological models of the BBB.
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Affiliation(s)
- James G Shamul
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
- RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Zhiyuan Wang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | - Hyeyeon Gong
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | - Wenquan Ou
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | - Alisa M White
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
| | | | - Shuo Gu
- RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Alisa Morss Clyne
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA
- Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, MD, USA
- Brain and Behavior Institute, University of Maryland, College Park, MD, USA
| | | | - Xiaoming He
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
- Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, MD, USA.
- Brain and Behavior Institute, University of Maryland, College Park, MD, USA.
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA.
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20
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Fakhri Bafghi MS, Khoshnam Rad N, Roostaei G, Nikfar S, Abdollahi M. The reality of modeling irritable bowel syndrome: progress and challenges. Expert Opin Drug Discov 2025; 20:433-445. [PMID: 40162721 DOI: 10.1080/17460441.2025.2481264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 03/14/2025] [Indexed: 04/02/2025]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is often therapeutically challenging. While research has advanced our understanding of IBS pathophysiology, developing precise models to predict drug response and treatment outcomes remains a significant hurdle. AREAS COVERED This perspective provides an overview of the use of animal models alongside cutting-edge technologies used to bring drugs from bench to bedside.Furthermore, the authors examine the progress and limitations of IBS modeling. The authors further discuss the challenges of traditional animal models and gives a spotlight to the potential of innovative technologies, such as organ-on-chip systems, computational models, and artificial intelligence (AI). These approaches intend to enhance both the understanding and treatment of IBS. EXPERT OPINION Although animal models have been central to understanding IBS research, they have limitations. The future of IBS research resides in integrating organ-on-chip systems and utilizing modern technological developments, such as AI. These tools will enable the design of more effective treatment strategies and improve patients' overall well-being. To achieve this, collaboration between experts from various disciplines is essential to improve these models and guarantee their clinical application and reliability.
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Affiliation(s)
- Maryam S Fakhri Bafghi
- Department of Internal Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Niloofar Khoshnam Rad
- Thoracic Research Center, Imam Khomeini Hospital Complex, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Ghazal Roostaei
- Thoracic Research Center, Imam Khomeini Hospital Complex, Tehran, Iran
- Rasoul Akram Hospital Clinical Research Development Center, School of Medicine, Rasool Akram Medical Complex, Iran University of Medical Sciences, Tehran, Iran
| | - Shekoufeh Nikfar
- Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
- Personalized Medicine Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mohammad Abdollahi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
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21
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Kunze M, Malfatti F. Towards a Conceptual Framework to Better Understand the Advantages and Limitations of Model Organisms. Eur J Neurosci 2025; 61:e70071. [PMID: 40165014 DOI: 10.1111/ejn.70071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 02/20/2025] [Accepted: 03/05/2025] [Indexed: 04/02/2025]
Abstract
Model organisms (MO) are widely used in neuroscience to study brain processes, behavior, and the biological foundation of human diseases. However, the use of MO has also been criticized for low reliability and insufficient success rate in the development of therapeutic approaches, because the success of MO use also led to overoptimistic and simplistic applications, which sometimes resulted in wrong conclusions. Here, we develop a conceptual framework of MO to support scientists in their practical work and to foster discussions about their power and limitations. For this purpose, we take advantage of concepts developed in the philosophy of science and adjust them for practical application by neuroscientists. We suggest that MO can be best understood as tools that are used to gain information about a group of species or a phenomenon in a species of interest. These learning processes are made possible by some properties of MO, which facilitate the process of acquisition of understanding or provide practical advantages, and the possibility to transfer information between species. However, residual uncertainty in the reliability of information transfer remains, and incorrect generalizations can be side-effects of epistemic benefits, which we consider as representational and epistemic risks. This suggests that to use MO most effectively, scientists should analyze the similarity relation between the involved species, weigh advantages and risks of certain epistemic benefits, and invest in carefully designed validation experiments. Altogether, our analysis illustrates how scientists can benefit from philosophical concepts for their research practice.
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Affiliation(s)
- Markus Kunze
- Center for Brain Research, Department of Pathobiology of the Nervous System, Medical University of Vienna, Vienna, Austria
| | - Federica Malfatti
- Institut für Christliche Philosophie, University of Innsbruck, Innsbruck, Austria
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22
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SoRelle ED, Luftig MA. Multiple sclerosis and infection: history, EBV, and the search for mechanism. Microbiol Mol Biol Rev 2025; 89:e0011923. [PMID: 39817754 PMCID: PMC11948499 DOI: 10.1128/mmbr.00119-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2025] Open
Abstract
SUMMARYInfection has long been hypothesized as the cause of multiple sclerosis (MS), and recent evidence for Epstein-Barr virus (EBV) as the trigger of MS is clear and compelling. This clarity contrasts with yet uncertain viral mechanisms and their relation to MS neuroinflammation and demyelination. As long as this disparity persists, it will invigorate virologists, molecular biologists, immunologists, and clinicians to ascertain how EBV potentiates MS onset, and possibly the disease's chronic activity and progression. Such efforts should take advantage of the diverse body of basic and clinical research conducted over nearly two centuries since the first clinical descriptions of MS plaques. Defining the contribution of EBV to the complex and multifactorial pathology of MS will also require suitable experimental models and techniques. Such efforts will broaden our understanding of virus-driven neuroinflammation and specifically inform the development of EBV-targeted therapies for MS management and, ultimately, prevention.
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Affiliation(s)
- Elliott D. SoRelle
- Department of Molecular Genetics & Microbiology, Center for Virology, Duke University, Durham, North Carolina, USA
| | - Micah A. Luftig
- Department of Molecular Genetics & Microbiology, Center for Virology, Duke University, Durham, North Carolina, USA
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23
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Willis ML, Seim R, Herring LE, Mordant AL, Webb TS, Upchurch GR, Sharma AK, Cairns BA, Efron P, Wallet SM, Coleman LG, Maile R. Temporal changes in the protein cargo of extracellular vesicles and resultant immune reprogramming after severe burn injury in humans and mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.19.644202. [PMID: 40166336 PMCID: PMC11957110 DOI: 10.1101/2025.03.19.644202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Introduction Severe injury, including burn trauma, leads to profound immune dysfunction, yet the mechanisms driving these changes remain incompletely defined. This lack of understanding has hindered efforts to modulate the immune response effectively. Additionally, a clear biomarker profile to guide clinicians in identifying burn patients at high risk for poor clinical outcomes is lacking. Extracellular vesicles (EVs) have emerged as novel mediators of immune dysfunction in various pathologies. Prior studies in mouse models have demonstrated that plasma EVs increase following burn injury and contribute to immune dysfunction. Furthermore, EVs have potential as biomarkers for predicting extended hospital stays in burn patients. This study hypothesizes that human EVs, purified early and late after burn injury, will exhibit immune reprogramming effects similar to those observed in mice and that specific EV protein cargo may serve as biomarkers of immune and physiological responses to burn injury. Methods EVs were isolated from the plasma of burn-injury patients at early (<72h) and late (≥14 days) time points post-injury. Using unbiased immune transcriptome and bioinformatic causal network analyses, the immunomodulatory effects of these EVs were assessed in human THP-1 macrophages. Mass spectrometry-based quantitative proteomics and pathway analyses were conducted to characterize the protein cargo of EVs from both human and mouse models at different post-burn phases. Results Early post-burn human EVs induced significant immune reprogramming in macrophages, increasing pro-inflammatory signaling while suppressing anti-inflammatory pathways. In contrast, late post-burn EVs exhibited an immunosuppressive profile, with downregulation of pro-inflammatory pathways and upregulation of anti-inflammatory signaling. Proteomic analyses revealed that human and mouse EVs contained unique and overlapping protein cargo across different time points. At day 7 post-burn, mouse EVs were enriched in circulation/complement and neuronal proteins, whereas by day 14, reductions in membrane and metabolism-associated proteins were observed. Similarly, in human EVs at 14 days post-burn, increased levels of circulation/complement, immune, and transport proteins were detected. Conclusions EVs from burn-injury patients at distinct time points differentially modulate immune responses in macrophages, mirroring the temporal immune phenotypes observed in clinical settings. These findings suggest that EV-macrophage interactions play a crucial role in burn-induced immune dysfunction and highlight the potential of EV protein cargo as biomarkers for immune status and patient outcomes following burn injury.
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Affiliation(s)
- Micah L. Willis
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA
- Curriculum in Toxicology and Environmental Medicine, School of Medicine, North Carolina, Chapel Hill, NC, USA
| | - Roland Seim
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA
| | - Laura E. Herring
- UNC Proteomic Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Angie L. Mordant
- UNC Proteomic Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Thomas S. Webb
- UNC Proteomic Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Ashish K. Sharma
- Department of Surgery, University of Florida, Gainesville, FL, USA
| | - Bruce A. Cairns
- North Carolina Jaycee Burn Center, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Philip Efron
- Department of Surgery, University of Florida, Gainesville, FL, USA
- Sepsis and Critical Illness Research Center, Department of Surgery, University of Florida, Gainesville, FL, USA
| | - Shannon M. Wallet
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA
| | - Leon G. Coleman
- Curriculum in Toxicology and Environmental Medicine, School of Medicine, North Carolina, Chapel Hill, NC, USA
- Bowles Center for Alcohol Studies, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Robert Maile
- Department of Surgery, University of Florida, Gainesville, FL, USA
- Sepsis and Critical Illness Research Center, Department of Surgery, University of Florida, Gainesville, FL, USA
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24
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Nelson JL, Lambert NC. The when, what, and where of naturally-acquired microchimerism. Semin Immunopathol 2025; 47:20. [PMID: 40067465 DOI: 10.1007/s00281-024-01029-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 11/14/2024] [Indexed: 05/13/2025]
Abstract
Naturally acquired microchimerism (Mc) is increasingly recognized as an aspect of normal biology. Maternal-fetal bi-directional exchange during pregnancy creates a Mc legacy for the long-term in both individuals. Maternal Mc in her offspring and Mc of fetal origin in women with previous births are best studied. Other sources include from a known or vanished twin, miscarriage or pregnancy termination, older sibling, or previous maternal pregnancy loss. Mc is pleotropic and protean, present in diverse forms, and changing over time as other aspects of biology. Mc acquired from multiple sources, at different lifespan times, and taking on an array of diverse forms, creates a "forward, reverse, and horizontal inheritance" Mc landscape. Mc is found in adaptive and innate immune cells, as resident tissue-specific cells in a wide variety of human tissues, and among other forms as extracellular vesicles. HLA molecules function in a myriad of ways as key determinants for health and are of central importance in interactions between genetically disparate individuals. Studies of autoimmune disease have firmly established a primary role of HLA molecules. Studies of iatrogenic chimerism have established benefit of donor-recipient HLA-disparity against recurrent malignancy after transplantation. HLA molecules and HLA-relationships of families are therefore of particular interest in seeking to understand the role(s) of Mc at the interface of auto-immunity and healthy allo-immunity. This review will begin by providing perspective on Mc in biology followed by a primary focus on persistent Mc according to the human lifespan, in healthy individuals and with illustrative examples of autoimmune diseases.
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Affiliation(s)
- J Lee Nelson
- Department of Medicine, University of Washington, Seattle, WA, USA.
- Translational Science and Therapeutics Fred Hutchinson Cancer Center, Seattle, USA.
| | - Nathalie C Lambert
- INSERM UMRs 1097 Arthrites, Microchimérisme et Inflammations (ARTHEMIS), Aix Marseille Université, Marseille, France.
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25
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Kühtreiber H, Bormann D, Salek M, Auer L, Haider T, Mildner CS, Lingitz MT, Aigner C, Radtke C, Zimpfer D, Ankersmit HJ, Mildner M. Burn-Related Glycocalyx Derangement and the Emerging Role of MMP8 in Syndecan Shedding. BIOLOGY 2025; 14:269. [PMID: 40136525 PMCID: PMC11940132 DOI: 10.3390/biology14030269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/26/2025] [Accepted: 03/04/2025] [Indexed: 03/27/2025]
Abstract
Burn injuries often lead to severe complications, including acute respiratory distress syndrome (ARDS), driven in part by systemic inflammation and glycocalyx disruption. In this study, we analyzed the sera of 28 patients after burn trauma and utilized single-cell RNA sequencing (scRNA-seq) along with microarray transcriptomic analysis to decipher the impact of burn injury on glycocalyx derangement. We observed the significant upregulation of immune cell-derived degrading enzymes, particularly matrix metalloproteinase-8 (MMP8), which correlated with increased immune cell infiltration and glycocalyx derangement. Serum analyses of burn patients revealed significantly elevated levels of shed glycocalyx components and MMP8, both correlating with the presence of inhalation injury. Consequently, the treatment of human in vitro lung tissue models with MMP8 induced significant glycocalyx shedding in alveolar epithelial cells. Together, based on these findings, we propose that MMP8 plays a previously unrecognized role in glycocalyx disruption and subsequent lung injury post-burn, which implies that inhibiting MMP8 may represent a promising therapeutic strategy for alleviating lung injury after burn trauma.
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Affiliation(s)
- Hannes Kühtreiber
- Department of Thoracic Surgery, Applied Immunology Laboratory, Medical University of Vienna, 1090 Vienna, Austria
- Aposcience AG, 1200 Vienna, Austria
- Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria
- Comprehensive Center for Chest Diseases, Medical University of Vienna, 1090 Vienna, Austria
| | - Daniel Bormann
- Department of Thoracic Surgery, Applied Immunology Laboratory, Medical University of Vienna, 1090 Vienna, Austria
- Aposcience AG, 1200 Vienna, Austria
- Comprehensive Center for Chest Diseases, Medical University of Vienna, 1090 Vienna, Austria
- Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria
| | - Melanie Salek
- Aposcience AG, 1200 Vienna, Austria
- Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria
| | - Lisa Auer
- Department of Thoracic Surgery, Applied Immunology Laboratory, Medical University of Vienna, 1090 Vienna, Austria
- Aposcience AG, 1200 Vienna, Austria
| | - Thomas Haider
- Department of Orthopedics and Trauma Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Caterina Selina Mildner
- Department of Thoracic Surgery, Applied Immunology Laboratory, Medical University of Vienna, 1090 Vienna, Austria
| | - Marie-Therese Lingitz
- Division of General Anesthesia and Intensive Care Medicine, Department of Anesthesia, Critical Care and Pain Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Clemens Aigner
- Department of Thoracic Surgery, Applied Immunology Laboratory, Medical University of Vienna, 1090 Vienna, Austria
- Comprehensive Center for Chest Diseases, Medical University of Vienna, 1090 Vienna, Austria
| | - Christine Radtke
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Daniel Zimpfer
- Department of Cardiac Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Hendrik Jan Ankersmit
- Department of Thoracic Surgery, Applied Immunology Laboratory, Medical University of Vienna, 1090 Vienna, Austria
- Aposcience AG, 1200 Vienna, Austria
- Comprehensive Center for Chest Diseases, Medical University of Vienna, 1090 Vienna, Austria
| | - Michael Mildner
- Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria
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26
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Cayford J, Atteberry B, Singh-Taylor A, Retter A, Berman BP, Kelly TK. Chromatin changes associated with neutrophil extracellular trap formation in whole blood reflect complex immune signaling. Front Immunol 2025; 16:1515430. [PMID: 40103826 PMCID: PMC11914908 DOI: 10.3389/fimmu.2025.1515430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 02/03/2025] [Indexed: 03/20/2025] Open
Abstract
Background Neutrophils are key players in innate immunity, forming neutrophil extracellular traps (NETs) to defend against infections. However, excess NET formation is implicated in inflammatory conditions such as sepsis and immunothrombosis. Studying NET formation in isolated neutrophils provides important mechanistic insights but does not reflect the complexity of immune interactions in whole blood, limiting our understanding of neutrophil responses. Methods This study investigates chromatin accessibility changes using Assay for Transposase-Accessible Chromatin with sequencing (ATAC-Seq) during phorbol 12-myristate 13-acetate (PMA) induced NET formation in whole blood. We compared chromatin accessibility patterns in neutrophils following PMA treatment in isolation and whole blood to assess the impact of other immune cells and signaling environment. Results Whole blood PMA stimulation elicited consistent chromatin accessibility changes across donors, demonstrating organized chromatin decondensation during NET formation. The chromatin response was characterized by increased accessibility in genomic regions enriched for immune-specific pathways, highlighting the role of immune cell interactions in NET formation. Differentially accessible regions (DARs) present following PMA induction in whole blood and isolated neutrophils showed greater association with NET-related and inflammatory transcription factors, while DARs specific to isolated neutrophils showed fewer relevant motifs. Pathway analysis indicated that whole blood responses involved more robust activation of immune-specific pathways, such as interleukin and cytokine signaling, compared to isolated neutrophils. Conclusions Our findings underscore the importance of studying NET formation within a whole blood environment to capture the complexity of neutrophil responses and immune cell interactions. This understanding is crucial for identifying effective therapeutic targets in NET-associated inflammatory diseases.
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Affiliation(s)
- Justin Cayford
- Innovation Lab, Volition America, Carlsbad, CA, United States
| | | | | | - Andrew Retter
- Innovation Lab, Volition America, Carlsbad, CA, United States
- Volition Diagnostics UK Limited, London, United Kingdom
- School of Immunology and Microbial Sciences, King's College, London, United Kingdom
| | - Benjamin P. Berman
- Innovation Lab, Volition America, Carlsbad, CA, United States
- Department of Developmental Biology and Cancer Research, The Hebrew University of Jerusalem, Jerusalem, Israel
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27
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Lopes CF, Laurent E, Caul-Futy M, Dubois J, Mialon C, Chojnacki C, Sage E, Boda B, Huang S, Rosa-Calatrava M, Constant S. A Novel In Vitro Primary Human Alveolar Model (AlveolAir™) for H1N1 and SARS-CoV-2 Infection and Antiviral Screening. Microorganisms 2025; 13:572. [PMID: 40142465 PMCID: PMC11944821 DOI: 10.3390/microorganisms13030572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 03/28/2025] Open
Abstract
Lower respiratory infections, mostly caused by viral or bacterial pathogens, remain a leading global cause of mortality. The differences between animal models and humans contribute to inefficiencies in drug development, highlighting the need for more relevant and predictive, non-animal models. In this context, AlveolAir™, a fully primary in vitro 3D human alveolar model, was characterized and demonstrated the sustained presence of alveolar type I (ATI) and type II (ATII) cells. This model exhibited a functional barrier over a 30-day period, evidenced by high transepithelial electrical resistance (TEER). These findings were further validated by tight junctions' confocal microscopy and low permeability to Lucifer yellow, confirming AlveolAir™ as robust platform for drug transport assays. Additionally, successful infections with H1N1 and SARS-CoV-2 viruses were achieved, and antiviral treatments with Baloxavir and Remdesivir, respectively, effectively reduced viral replication. Interestingly, both viruses infected only the epithelial layer without replicating in endothelial cells. These findings indicate AlveolAir™ as a relevant model for assessing the toxicity and permeability of xenobiotics and evaluating the efficacy of novel antiviral therapies.
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Affiliation(s)
| | - Emilie Laurent
- CIRI, Centre International de Recherche en Infectiologie, Team VirPath, Inserm, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France; (E.L.); (J.D.); (C.M.); (M.R.-C.)
- Virnext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, 69008 Lyon, France
- International Research Laboratory RespiVir France-Canada, Centre de Recherche en Infectiologie, Faculté de Médecine RTH Laennec Université Claude Bernard Lyon 1, INSERM, CNRS, ENS de Lyon, 69008 Lyon, France
| | - Mireille Caul-Futy
- Epithelix,1228 Geneva, Switzerland; (C.F.L.); (M.C.-F.); (C.C.); (B.B.); (S.H.)
| | - Julia Dubois
- CIRI, Centre International de Recherche en Infectiologie, Team VirPath, Inserm, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France; (E.L.); (J.D.); (C.M.); (M.R.-C.)
- Virnext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, 69008 Lyon, France
- International Research Laboratory RespiVir France-Canada, Centre de Recherche en Infectiologie, Faculté de Médecine RTH Laennec Université Claude Bernard Lyon 1, INSERM, CNRS, ENS de Lyon, 69008 Lyon, France
| | - Chloé Mialon
- CIRI, Centre International de Recherche en Infectiologie, Team VirPath, Inserm, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France; (E.L.); (J.D.); (C.M.); (M.R.-C.)
- Virnext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, 69008 Lyon, France
- International Research Laboratory RespiVir France-Canada, Centre de Recherche en Infectiologie, Faculté de Médecine RTH Laennec Université Claude Bernard Lyon 1, INSERM, CNRS, ENS de Lyon, 69008 Lyon, France
| | - Caroline Chojnacki
- Epithelix,1228 Geneva, Switzerland; (C.F.L.); (M.C.-F.); (C.C.); (B.B.); (S.H.)
| | | | - Bernadett Boda
- Epithelix,1228 Geneva, Switzerland; (C.F.L.); (M.C.-F.); (C.C.); (B.B.); (S.H.)
| | - Song Huang
- Epithelix,1228 Geneva, Switzerland; (C.F.L.); (M.C.-F.); (C.C.); (B.B.); (S.H.)
| | - Manuel Rosa-Calatrava
- CIRI, Centre International de Recherche en Infectiologie, Team VirPath, Inserm, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France; (E.L.); (J.D.); (C.M.); (M.R.-C.)
- Virnext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, 69008 Lyon, France
- International Research Laboratory RespiVir France-Canada, Centre de Recherche en Infectiologie, Faculté de Médecine RTH Laennec Université Claude Bernard Lyon 1, INSERM, CNRS, ENS de Lyon, 69008 Lyon, France
- Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec, Université Laval, Québec, QC G1V 4G2, Canada
| | - Samuel Constant
- Epithelix,1228 Geneva, Switzerland; (C.F.L.); (M.C.-F.); (C.C.); (B.B.); (S.H.)
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28
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Pilalis E, Zisis D, Andrinopoulou C, Karamanidou T, Antonara M, Stavropoulos TG, Chatziioannou A. Genome-wide functional annotation of variants: a systematic review of state-of-the-art tools, techniques and resources. Front Pharmacol 2025; 16:1474026. [PMID: 40098614 PMCID: PMC11911558 DOI: 10.3389/fphar.2025.1474026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 02/03/2025] [Indexed: 03/19/2025] Open
Abstract
The recent advancement of sequencing technologies marks a significant shift in the character and complexity of the digital genomic data universe, encompassing diverse types of molecular data, screened through manifold technological platforms. As a result, a plethora of fully assembled genomes are generated that span vertically the evolutionary scale. Notwithstanding the tsunami of thriving innovations that accomplish unprecedented, nucleotide-level, structural and functional annotation, an exhaustive, systemic, massive genome-wide functional annotation remains elusive, particularly when the criterion is automation and efficiency in data-agnostic interpretation. The latter is of paramount importance for the elaboration of strategies for sophisticated, data-driven genome-wide annotation, which aim to impart a sustainable and comprehensive systemic approach to addressing whole genome variation. Therefore, it is essential to develop methods and tools that promote systematic functional genomic annotation, with emphasis on mechanistic information exceeding the limits of coding regions, and exploiting the chunks of pertinent information residing in non-coding regions, including promoter and enhancer sequences, non-coding RNAs, DNA methylation sites, transcription factor binding sites, transposable elements and more. This review provides an overview of the current state-of-the-art in genome-wide functional annotation of genetic variation, including existing bioinformatic tools, resources, databases and platforms currently available or reported in the literature. Particular emphasis is placed on the functional annotation of variants that lie outside protein-coding genomic regions (intronic or intergenic), their potential co-localization with regulatory element areas, such as putative non-coding RNA regions, and the assessment of their functional impact on the investigated phenotype. In addition, state-of-the-art tools that leverage data obtained from WGS and GWAS-based analyses are discussed, along with future bioinformatics directions and developments. These future directions emphasize efficient, comprehensive, and largely automated functional annotation of both coding and non-coding genomic variants, as well as their optimal evaluation.
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Affiliation(s)
| | | | | | | | - Maria Antonara
- Pfizer Center for Digital Innovation, Thessaloniki, Greece
| | | | - Aristotelis Chatziioannou
- e-NIOS Applications PC, Kallithea, Greece
- Biomedical Research Foundation of the Academy of Athens, Athens, Greece
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29
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Sahoo SS, Khiami M, Wlodarski MW. Inducible pluripotent stem cell models to study bone marrow failure and MDS predisposition syndromes. Exp Hematol 2025; 143:104669. [PMID: 39491640 DOI: 10.1016/j.exphem.2024.104669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/24/2024] [Accepted: 10/26/2024] [Indexed: 11/05/2024]
Abstract
Induced pluripotent stem cells (iPSCs) have emerged as powerful tools for in vitro modeling of bone marrow failure (BMF) syndromes and hereditary conditions predisposing to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). This review synthesizes recent advances in iPSC-based disease modeling for various inherited BMF/MDS disorders, including Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia syndrome, Shwachman-Diamond syndrome, and severe congenital neutropenia as well as GATA2, RUNX1, ETV6, ANKRD26, SAMD9, SAMD9L, and ADH5/ALDH2 syndromes. Although the majority of these iPSC lines are derived from patient cells, some are generated by introducing patient-specific mutations into healthy iPSC backgrounds, offering complementary approaches to disease modeling. The review highlights the ability of iPSCs to recapitulate key disease phenotypes, such as impaired hematopoietic differentiation, telomere dysfunction, and defects in DNA repair or ribosome biogenesis. We discuss how these models have enhanced our understanding of disease pathomechanisms, hematopoietic defects, and potential therapeutic approaches. Challenges in generating and maintaining disease-specific iPSCs are examined, particularly for disorders involving DNA repair. We emphasize the necessity of creating isogenic controls to elucidate genotype-phenotype relationships. Furthermore, we address limitations of current iPSC models, including genetic variability among iPSC clones derived from the same patient, and difficulties in achieving robust engraftment of iPSC-derived hematopoietic progenitor cells in mouse transplantation models. The review also explores future directions, including the potential of iPSC models for drug discovery and personalized medicine approaches. This review underscores the significance of iPSC technology in advancing our understanding of inherited hematopoietic disorders and its potential to inform novel therapeutic strategies.
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Affiliation(s)
- Sushree S Sahoo
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN
| | - Majd Khiami
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN
| | - Marcin W Wlodarski
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN.
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30
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Yang J, Xie YF, Smith R, Ratté S, Prescott SA. Discordance between preclinical and clinical testing of Na V 1.7-selective inhibitors for pain. Pain 2025; 166:481-501. [PMID: 39928833 PMCID: PMC11808711 DOI: 10.1097/j.pain.0000000000003425] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/19/2024] [Accepted: 08/13/2024] [Indexed: 10/26/2024]
Abstract
ABSTRACT The voltage-gated sodium channel Na V 1.7 plays an important role in pain processing according to genetic data. Those data made Na V 1.7 a popular drug target, especially since its relatively selective expression in nociceptors promised pain relief without the adverse effects associated with broader sodium channel blockade. Despite encouraging preclinical data in rodents, Na V 1.7-selective inhibitors have not yet proven effective in clinical trials. Discrepancies between preclinical and clinical results should raise alarms. We reviewed preclinical and clinical reports on the analgesic efficacy of Na V 1.7-selective inhibitors and found critical differences in several factors. Putting aside species differences, most preclinical studies tested young male rodents with limited genetic variability, inconsistent with the clinical population. Inflammatory pain was the most common preclinical chronic pain model whereas nearly all clinical trials focused on neuropathic pain despite some evidence suggesting Na V 1.7 channels are not essential for neuropathic pain. Preclinical studies almost exclusively measured evoked pain whereas most clinical trials assessed average pain intensity without distinguishing between evoked and spontaneous pain. Nearly all preclinical studies gave a single dose of drug unlike the repeat dosing used clinically, thus precluding preclinical data from demonstrating whether tolerance or other slow processes occur. In summary, preclinical testing of Na V 1.7-selective inhibitors aligned poorly with clinical testing. Beyond issues that have already garnered widespread attention in the pain literature, our results highlight the treatment regimen and choice of pain model as areas for improvement.
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Affiliation(s)
- Jane Yang
- Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Yu-Feng Xie
- Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
| | - Russell Smith
- Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
| | - Stéphanie Ratté
- Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
| | - Steven A. Prescott
- Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
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31
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Mattingly Z, Chetty S. Untangling the Molecular Mechanisms Contributing to Autism Spectrum Disorder Using Stem Cells. Autism Res 2025; 18:476-485. [PMID: 39989339 DOI: 10.1002/aur.70005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 02/06/2025] [Accepted: 02/08/2025] [Indexed: 02/25/2025]
Abstract
Autism spectrum disorder (ASD) is a complex neuro developmental condition characterized by significant genetic and phenotypic variability, making diagnosis and treatment challenging. The heterogeneity of ASD-associated genetic variants and the absence of clear causal factors in many cases complicate personalized care. Traditional models, such as postmortem brain tissue and animal studies, have provided valuable insights but are limited in capturing the dynamic processes and human-specific aspects of ASD pathology. Recent advances in human induced pluripotent stem cell (iPSC) technology have transformed ASD research by enabling the generation of patient-derived neural cells in both two-dimensional cultures and three-dimensional brain organoid models. These models retain the donor's genetic background, allowing researchers to investigate disease-specific cellular and molecular mechanisms while identifying potential therapeutic targets tailored to individual patients. This commentary highlights how stem cell-based approaches are advancing our understanding of ASD and paving the way for more personalized diagnostic and therapeutic strategies.
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Affiliation(s)
- Zoe Mattingly
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Sundari Chetty
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Cambridge, Massachusetts, USA
- Lurie Center for Autism, Massachusetts General Hospital, Boston, Massachusetts, USA
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Bukhari MMM, Khabooshani M, Naqvi SM, McNamara LM. Estrogen deficiency alters vascularization and mineralization dynamics: insight from a novel 3-D humanized and vascularized bone organoid model. Am J Physiol Cell Physiol 2025; 328:C743-C756. [PMID: 39819034 DOI: 10.1152/ajpcell.00738.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/24/2024] [Accepted: 01/04/2025] [Indexed: 01/19/2025]
Abstract
Osteoporosis is not merely a disease of bone loss but also involves changes in the mineral composition of the bone that remains. In vitro studies have investigated these changes and revealed that estrogen deficiency alters osteoblast mineral deposition, osteocyte mechanosensitivity, and osteocyte regulation of osteoclastogenesis. During healthy bone development, vascular cells stimulate bone mineralization via endochondral ossification, but estrogen deficiency impairs vascularization. Yet, existing in vitro bone models overlook the role of vascular cells in osteoporosis pathology. Thus, here we 1) develop an advanced three-dimensional (3-D) vascularized, mineralized, and humanized bone model following the endochondral ossification process, and 2) apply this model to mimic postmenopausal estrogen withdrawal and provide a mechanistic understanding of changes in vascularization and bone mineralization in estrogen deficiency. We confirmed the successful development of a vascularized and mineralized human bone model via endochondral ossification, which induced the self-organization of vasculature, associated with hypertrophy (collagen X), and promoted mineralization. When the model was applied to study estrogen deficiency, we reported the development of distinct vessel-like structures (CD31+) in the postmenopausal 3-D constructs. Moreover, during estrogen withdrawal vascularized bone demonstrated a significant increase in mineral deposition and apoptosis, which did not occur in nonvascularized bone. These findings reveal a potential mechanism for bone mineral heterogeneity in osteoporotic bone, whereby vascularized bone becomes highly mineralized whereas in nonvascularized regions this effect is not observed.NEW & NOTEWORTHY Here we develop an in vitro three-dimensional (3-D) vascularized and humanized bone model following an endochondral ossification approach. We applied the model to recapitulate estrogen deficiency as representative of the osteoporotic phenotype. The results of this study reveal that estrogen deficiency exacerbates formation of 3-D vessel-like structures in vascularized models and thereby drives mineral deposition.
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Affiliation(s)
- Muhammad M M Bukhari
- Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, College of Science and Engineering, University of Galway, Galway, Ireland
| | - Mostafa Khabooshani
- Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, College of Science and Engineering, University of Galway, Galway, Ireland
| | - Syeda M Naqvi
- Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, College of Science and Engineering, University of Galway, Galway, Ireland
| | - Laoise M McNamara
- Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, College of Science and Engineering, University of Galway, Galway, Ireland
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33
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Frost MR, Ball BK, Pendyala M, Douglas SR, Brubaker DK, Chan DD. Computational Translation of Mouse Models of Osteoarthritis Predicts Human Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.23.639777. [PMID: 40060529 PMCID: PMC11888325 DOI: 10.1101/2025.02.23.639777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Objective Translation of biological insights from preclinical studies to human disease is a pressing challenge in biomedical research, including in osteoarthritis. Translatable Components Regression (TransComp-R) is a computational framework that has previously been used to synthesize preclinical and human OA data to identify biological pathways predictive of human disease conditions. We aimed to evaluate the translatability of two common murine models of post-traumatic osteoarthritis - surgical destabilization of the medial meniscus (DMM) and noninvasive anterior cruciate ligament rupture (ACLR) - to transcriptomics cartilage data from human OA outcomes. Design Transcriptomics cartilage data of DMM and ACLR mouse and human data was acquired from Gene Expression Omnibus. TransComp-R was used to project human OA data into a mouse model (DMM or ACLR) principal component analysis space. The principal components (PCs) were regressed against human OA conditions using increasing complexity of linear regression models incorporating human demographic covariates of OA, sex, and age. Biological pathways of the mouse PCs that significantly stratified human OA and control groups were then interpreted using Gene Set Enrichment Analysis. Results From the TransComp-R model, we identified different enriched biological pathways across DMM and ACLR models. While PCs among the DMM models revealed pathways associated with cell signaling and metabolism, ACLR PCs represented immune function and cellular pathways associated with OA condition. The immune pathways presented in the ACLR further highlighted the potential relevance of the OA pathways observed in human conditions. Conclusions The ACLR mouse model more successfully predicted human OA conditions, particularly with the human control groups without a history of joint injury or disease. Cross-species translational approaches support the selection of preclinical models intended for therapeutic discovery and pathway analysis in humans.
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Affiliation(s)
- Maya R Frost
- Weldon School of Biomedical Engineering, Purdue University
| | - Brendan K Ball
- Weldon School of Biomedical Engineering, Purdue University
| | - Meghana Pendyala
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute
| | | | - Douglas K Brubaker
- Center for Global Health and Diseases, Department of Pathology, School of Medicine, Case Western Reserve University
- Blood Heart Lung Immunology Research Center, University Hospitals Cleveland Medical Center
| | - Deva D Chan
- Weldon School of Biomedical Engineering, Purdue University
- School of Mechanical Engineering, Purdue University
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34
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Hennessy Garza R, Mahoney JE, Burns M, Quanbeck A. Connecting the bibliographic-directed citation networks of translational research and implementation science. J Clin Transl Sci 2025; 9:e64. [PMID: 40201632 PMCID: PMC11975788 DOI: 10.1017/cts.2025.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 01/14/2025] [Accepted: 01/16/2025] [Indexed: 04/10/2025] Open
Abstract
Introduction Translational science and implementation science are two disciplines that integrate scientific findings into practice within healthcare. One method to assess the integration of these fields is to review the academic crossover between the disciplines with respect to shared citations in the peer-reviewed literature. Methods This paper used direct citation network analysis to identify potential conceptual gaps and connections between the literature in implementation science and translational science. Bibliographic references were downloaded from Web of Science to create directed citation network maps in VosViewer. Heat maps visualized the top cited literature in each field. Results A literature search yielded 6,111 publications in translational science and 7,003 publications in implementation science. When all publications were combined in a directed citation network map, two separate groups of publications emerged, representing the two fields of implementation science and translational science. When the top 50 cited translational science publications were combined with implementation science publications, 14% had a 100%+ increase in citation links, 44% had a mean increase of 2.4%, and 42% shared no links. When the top 50 cited implementation science publications were combined with translational science publications, 2% had a 100%+ increase in citation links, 92% had a 3.3% mean increase, and 6% had no shared links. Conclusions Results suggest moderate academic overlap in the way published authors cite each other between translational science and implementation science. We hope the implications of this paper may promote continued collaborations between these fields to disseminate lessons learned and bridge research into practice more efficiently.
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Affiliation(s)
- Rose Hennessy Garza
- Joseph J Zilber College of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
| | - Jane E. Mahoney
- Department of Family Medicine and Community Health, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Morgan Burns
- Department of Family Medicine and Community Health, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Andrew Quanbeck
- Department of Family Medicine and Community Health, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
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35
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Nakagawa K, Yamazaki M, Tanimura H, Sakaguchi N, Kohara M, Sato I, Azuma M, Nishimoto-Kakiuchi A, Kato A, Kitazawa T, Konno R, Sankai T. Development of a novel postoperative adhesion induction model in cynomolgus monkeys with high reliability and reproducibility. Sci Rep 2025; 15:7102. [PMID: 40016251 PMCID: PMC11868379 DOI: 10.1038/s41598-025-88022-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 01/23/2025] [Indexed: 03/01/2025] Open
Abstract
Postoperative adhesions frequently occur following abdominal surgical interventions, leading to serious morbidities and requiring new therapeutic strategies. The development of new therapeutic agents to reduce postoperative adhesions needs animal models that closely mirror human pathophysiology. In this study, we established a novel surgical adhesion model in cynomolgus monkeys, which are characteristically similar to humans. Our model reliably and reproducibly developed adhesions. Histopathological analyses revealed that monkeys undergoing our novel surgery method exhibited changes consistent with those in monkeys that underwent open abdominal surgery. Furthermore, the cellular components of the adhesion tissue in our monkey model reflected those reported in human adhesion tissue. Furthermore, time-course transcriptomic analyses showed that our model accurately recapitulates the well-known progression cascade of postoperative adhesions. In addition, it identified the upregulation of gene that is absent in rodents. We expect our novel surgical method to be a promising tool for elucidating the detailed biology of postoperative adhesions and for assessing new therapeutic treatments with high translatability to human biology.
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Affiliation(s)
- Kenji Nakagawa
- Research Division, Chugai Pharmaceutical Co. Ltd., 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan.
| | - Masaki Yamazaki
- Translational Research Division, Chugai Pharmaceutical Co. Ltd., 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Hiromi Tanimura
- Research Division, Chugai Pharmaceutical Co. Ltd., 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Narumi Sakaguchi
- Research Division, Chugai Pharmaceutical Co. Ltd., 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Miho Kohara
- Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, 1-1 Hachimandai, Tsukuba-shi, Ibaraki, 305-0843, Japan
| | - Izumi Sato
- Research Division, Chugai Pharmaceutical Co. Ltd., 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Masahiro Azuma
- Research Division, Chugai Pharmaceutical Co. Ltd., 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Ayako Nishimoto-Kakiuchi
- Translational Research Division, Chugai Pharmaceutical Co. Ltd., 2-1-1 Nihonbashi-Muromachi Chuo-ku, Tokyo, 103-8324, Japan
| | - Atsuhiko Kato
- Translational Research Division, Chugai Pharmaceutical Co. Ltd., 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Takehisa Kitazawa
- Research Division, Chugai Pharmaceutical Co. Ltd., 216 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa, 244-8602, Japan
| | - Ryo Konno
- Department of Obstetrics and Gynecology, Jichi Medical University Saitama Medical Center, 1-847 Amanumacho, Omiya-ku, Saitama-shi, Saitama, 330-8503, Japan.
| | - Tadashi Sankai
- Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, 1-1 Hachimandai, Tsukuba-shi, Ibaraki, 305-0843, Japan.
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An L, Liu Y, Liu Y. Organ-on-a-Chip Applications in Microfluidic Platforms. MICROMACHINES 2025; 16:201. [PMID: 40047688 PMCID: PMC11857120 DOI: 10.3390/mi16020201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 02/06/2025] [Accepted: 02/08/2025] [Indexed: 03/09/2025]
Abstract
Microfluidic technology plays a crucial role in organ-on-a-chip (OoC) systems by replicating human physiological processes and disease states, significantly advancing biomedical research and drug discovery. This article reviews the design and fabrication processes of microfluidic devices. It also explores how these technologies are integrated into OoC platforms to simulate human physiological environments, highlighting key principles, technological advances, and diverse applications. Through case studies involving the simulation of multiple organs such as the heart, liver, and lungs, the article evaluates the impact of OoC systems' integrated microfluidic technology on drug screening, toxicity assessment, and personalized medicine. In addition, this article considers technical challenges, ethical issues, and future directions, and looks ahead to further optimizing the functionality and biomimetic precision of OoCs through innovation, emphasizing its critical role in promoting personalized medicine and precision treatment strategies.
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Affiliation(s)
- Ling An
- School of Engineering, Dali University, Dali 671003, China;
| | - Yi Liu
- School of Engineering, Dali University, Dali 671003, China;
| | - Yaling Liu
- Precision Medicine Translational Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Department of Bioengineering, Lehigh University, Bethlehem, PA 18015, USA
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Segal Y, Soltys J, Clarkson BDS, Howe CL, Irani SR, Pittock SJ. Toward curing neurological autoimmune disorders: Biomarkers, immunological mechanisms, and therapeutic targets. Neuron 2025; 113:345-379. [PMID: 39809275 DOI: 10.1016/j.neuron.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/26/2024] [Accepted: 12/04/2024] [Indexed: 01/16/2025]
Abstract
Autoimmune neurology is a rapidly expanding field driven by the discovery of neuroglial autoantibodies and encompassing a myriad of conditions affecting every level of the nervous system. Traditionally, autoantibodies targeting intracellular antigens are considered markers of T cell-mediated cytotoxicity, while those targeting extracellular antigens are viewed as pathogenic drivers of disease. However, recent advances highlight complex interactions between these immune mechanisms, suggesting a continuum of immunopathogenesis. The breakdown of immune tolerance, central to these conditions, is affected by modifiable and non-modifiable risk factors such as genetic predisposition, infections, and malignancy. While significant therapeutic advancements have revolutionized treatment of certain diseases, such as neuromyelitis optica, our understanding of many others, particularly T cell-mediated conditions, remains limited, with fewer treatment options available. Future research should focus on improving effector function modeling and deepening our understanding of the factors influencing immune tolerance, with the goal of providing novel treatment options and improving patient care.
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Affiliation(s)
- Yahel Segal
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA
| | - John Soltys
- Department of Neurosciences, Mayo Clinic, Jacksonville, FL, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA
| | - Benjamin D S Clarkson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA
| | - Charles L Howe
- Department of Neurology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA; Division of Experimental Neurology, Mayo Clinic, Rochester, MN, USA
| | - Sarosh R Irani
- Department of Neurosciences, Mayo Clinic, Jacksonville, FL, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA; Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
| | - Sean J Pittock
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA; Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA.
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Cohen SM, Boobis AR, Jacobson-Kram D, Schoeny R, Rosol TJ, Williams GM, Kaminski NE, Eichenbaum GM, Guengerich FP, Nash JF. Mode of action approach supports a lack of carcinogenic potential of six organic UV filters. Crit Rev Toxicol 2025; 55:248-284. [PMID: 40208192 DOI: 10.1080/10408444.2025.2462642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/06/2025] [Accepted: 01/10/2025] [Indexed: 04/11/2025]
Abstract
Ultraviolet (UV) filters, the active ingredients in sunscreens, have been used for several decades to reduce the risk of acute and chronic damage to the skin from solar UV radiation, which can lead to skin cancer. Based on recent clinical studies showing that certain UV filters are absorbed systemically at low levels in humans, the US Food and Drug Administration (FDA) has requested supplementing existing safety data with preclinical studies including oral and dermal 2-year rodent carcinogenicity studies. Although the conduct of 2-year rodent carcinogenicity studies has been the standard approach for evaluating the carcinogenic potential of chemicals and new drugs for approximately 6 decades, there are multiple examples showing that such studies are not predictive of human cancer risk. Given these concerns with 2-year rodent carcinogenicity studies, we have developed and applied an alternative approach for supplementing existing data related to carcinogenic potential for six of the most commonly used UV filters in sunscreen products (i.e. avobenzone, ensulizole, homosalate, octinoxate, octisalate, and octocrylene). This approach evaluates their mode of action (MOA) based on in vivo, in vitro, and in silico data combined with an assessment of exposure margins. This approach is based on the substantial progress in understanding the MOAs that are responsible for tumor induction in humans. It is consistent with those being developed by the International Council for Harmonization (ICH) and other health authorities to replace 2-year carcinogenicity studies given their limitations and questionable biological relevance to humans. The available data for the six UV filters show that they are not genotoxic and show no evidence of biologically relevant carcinogenic MOAs. Furthermore, their systemic exposure levels in humans fall well below concentrations at which they have biologic activity. In conclusion, these data support the continued safe use of these six filters in sunscreen products.
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Affiliation(s)
- Samuel M Cohen
- Department of Pathology, Immunology, and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Alan R Boobis
- National Heart & Lung Institute, Imperial College London, London, UK
| | | | | | - Thomas J Rosol
- Histology Core Facility and Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Gary M Williams
- Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, USA
| | - Norbert E Kaminski
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | | | - F Peter Guengerich
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - J F Nash
- Procter & Gamble, Mason, OH, USA
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Hu Y, Schnabl B, Stärkel P. Origin, Function, and Implications of Intestinal and Hepatic Macrophages in the Pathogenesis of Alcohol-Associated Liver Disease. Cells 2025; 14:207. [PMID: 39936998 PMCID: PMC11816606 DOI: 10.3390/cells14030207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 01/12/2025] [Accepted: 01/15/2025] [Indexed: 02/13/2025] Open
Abstract
Macrophages are members of the human innate immune system, and the majority reside in the liver. In recent years, they have been recognized as essential players in the maintenance of liver and intestinal homeostasis as well as key guardians of their respective immune systems, and they are increasingly being recognized as such. Paradoxically, they are also likely involved in chronic pathologies of the gastrointestinal tract and potentially in the alteration of the gut-liver axis in alcohol use disorder (AUD) and alcohol-associated liver disease (ALD). To date, the causal relationship between macrophages, the pathogenesis of ALD, and the immune dysregulation of the gut remains unclear. In this review, we will discuss our current understanding of the heterogeneity of intestinal and hepatic macrophages, their ontogeny, the potential factors that regulate their origin, and the evidence of how they are associated with the manifestation of chronic inflammation. We will also illustrate how the micro-environment of the intestine shapes the phenotypes and functionality of the macrophage compartment in both the intestines and liver and how they change during chronic alcohol abuse. Finally, we highlight the obstacles to current research and the prospects for this field.
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Affiliation(s)
- Yifan Hu
- Laboratory of Hepato-Gastroenterology, Institute of Clinical and Experimental Research, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA 92161, USA;
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA
| | - Peter Stärkel
- Laboratory of Hepato-Gastroenterology, Institute of Clinical and Experimental Research, Université Catholique de Louvain, 1200 Brussels, Belgium;
- Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
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40
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Elhaieg A, Farag A, Mandour AS, Hirose M, Elfadadny A, Tanaka R. Murine Models in Oral Research: A Narrative Review of Experimental Approaches and Cardiovascular Implications. BIOLOGY 2025; 14:127. [PMID: 40001895 PMCID: PMC11851954 DOI: 10.3390/biology14020127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/20/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025]
Abstract
Oral research using murine models spans a broad spectrum of studies, including investigations into oral infections such as periodontitis and peri-implantitis, wound healing, periodontal responses to orthodontic treatment, and occlusal overload. This review aims to provide a comprehensive overview of murine models employed in oral research, with a particular focus on their relevance in studying systemic implications, including cardiovascular diseases (CVDs). The objectives of this review are twofold: first, to highlight the diversity of experimental methods utilized in murine oral research, such as ligature placement, bacterial inoculation, surgical interventions, and mechanical manipulations; second, to explore how these models enhance our understanding of oral-systemic interactions. The findings demonstrate that murine models have significantly contributed to uncovering how oral conditions influence systemic health. Models of oral infections reveal pathways linking systemic inflammation, endothelial dysfunction, and atherogenesis, while studies on wound healing and mechanical stress offer valuable insights into periodontal tissue responses and regeneration under various conditions. These diverse findings underscore the versatility of murine models in addressing key questions across oral health research. By replicating human disease mechanisms, murine models serve as powerful tools for investigating the interplay between oral health and systemic diseases, including cardiovascular dysfunction. The insights gained from these models guide the development of integrated therapeutic approaches aimed at mitigating systemic inflammation and promoting periodontal regeneration.
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Affiliation(s)
- Asmaa Elhaieg
- Veterinary Teaching Hospital, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan; (A.F.)
| | - Ahmed Farag
- Veterinary Teaching Hospital, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan; (A.F.)
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Ahmed S. Mandour
- Department of Animal Medicine (Internal Medicine), Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Miki Hirose
- Veterinary Teaching Hospital, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan; (A.F.)
| | - Ahmed Elfadadny
- Laboratory of Internal Medicine, Cooperative Division of Veterinary Sciences, Tokyo University of Agriculture and Technology, Fuchu 183-0054, Japan
| | - Ryou Tanaka
- Veterinary Teaching Hospital, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan; (A.F.)
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Zhang R, Li G, Zhang Q, Wang Z, Xiang D, Zhang X, Chen J, Hutchins A, Qin D, Su H, Pei D, Li D. c-JUN: a chromatin repressor that limits mesoderm differentiation in human pluripotent stem cells. Nucleic Acids Res 2025; 53:gkaf001. [PMID: 39876710 PMCID: PMC11760979 DOI: 10.1093/nar/gkaf001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 12/24/2024] [Accepted: 01/03/2025] [Indexed: 01/30/2025] Open
Abstract
Cell fate determination at the chromatin level is not fully comprehended. Here, we report that c-JUN acts on chromatin loci to limit mesoderm cell fate specification as cells exit pluripotency. Although c-JUN is widely expressed across various cell types in early embryogenesis, it is not essential for maintaining pluripotency. Instead, it functions as a repressor to constrain mesoderm development while having a negligible impact on ectoderm differentiation. c-JUN interacts with MBD3-NuRD complex, which helps maintain chromatin in a low accessibility state at mesoderm-related genes during the differentiation of human pluripotent stem cells into mesoderm. Furthermore, c-JUN specifically inhibits the activation of key mesoderm factors, such as EOMES and GATA4. Knocking out c-JUN or inhibiting it with a JNK inhibitor can alleviate this suppression, promoting mesoderm cell differentiation. Consistently, knockdown of MBD3 enhances mesoderm generation, whereas MBD3 overexpression impedes it. Overexpressing c-JUN redirects differentiation toward a fibroblast-like lineage. Collectively, our findings suggest that c-JUN acts as a chromatin regulator to restrict the mesoderm cell fate.
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Affiliation(s)
- Ran Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao, 999078, China
| | - Guihuan Li
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, 621 Gangwan Road, Huangpu District, Guangzhou, Guangdong, 510799, China
| | - Qi Zhang
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, 621 Gangwan Road, Huangpu District, Guangzhou, Guangdong, 510799, China
| | - Zhenhua Wang
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, 621 Gangwan Road, Huangpu District, Guangzhou, Guangdong, 510799, China
| | - Dan Xiang
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Hong Kong Institute of Science & Innovation, Guangzhou Institutes of Biomedicine and Health, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China
| | - Xiaofei Zhang
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Hong Kong Institute of Science & Innovation, Guangzhou Institutes of Biomedicine and Health, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China
| | - Jiekai Chen
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Hong Kong Institute of Science & Innovation, Guangzhou Institutes of Biomedicine and Health, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China
| | - Andrew P Hutchins
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, 518055, China
| | - Dajiang Qin
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, 621 Gangwan Road, Huangpu District, Guangzhou, Guangdong, 510799, China
| | - Huanxing Su
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao, 999078, China
| | - Duanqing Pei
- Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, No. 600 Dunyu Road, Xihu District, Hangzhou, 310024, China
| | - Dongwei Li
- Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, 621 Gangwan Road, Huangpu District, Guangzhou, Guangdong, 510799, China
- Hainan Provincial Key Laboratory for human reproductive medicine and Genetic Research&Key Laboratory of Reproductive Health Diseases Research and Translation, Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, No. 3 Xueyuan Road, Longhua District, Haikou, Hainan, 571101, China
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Mathias FAS, Carvalho MGR, Ruiz JC. Therapeutic Vaccines for Hematological Cancers: A Scoping Review of This Immunotherapeutic Approach as Alternative to the Treatment of These Malignancies. Vaccines (Basel) 2025; 13:114. [PMID: 40006660 PMCID: PMC11860334 DOI: 10.3390/vaccines13020114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/17/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: The need for innovative cancer treatments has brought immunotherapies to the forefront as a promising approach, with therapeutic vaccines demonstrating the potential to mobilize immune cells to eliminate tumor cells. However, challenges such as genetic variability among patients, immune evasion mechanisms, and disease relapse contribute to the complexity of achieving an ideal therapy, especially for hematological cancers. This review systematically identifies and analyzes recent studies focused on the development of therapeutic immunotherapy vaccines, examining critical aspects such as development stages, key assays for therapeutic validation, treatment outcomes, and study limitations. Methods: A scoping review was conducted following the PRISMA extension guidelines (PRISMA-ScR). Literature searches were conducted across Scopus, PubMed, Web of Science, and Science Direct databases using keywords including "immunotherapy", "vaccines", "immunization", "hematological malignancies", "blood cancer", "hematopoietic neoplasms", and "leukemia". Results: A total of 56 articles published from 2013 to 2024 were included in the analysis. The majority of studies are in the preclinical stage, with some advancing to phase 1 and phase 2 clinical trials. Acute myeloid leukemia emerged as the most frequently studied malignancy. While first- and second-generation vaccines dominate the field, innovative approaches, such as dendritic-cell-based vaccines and mRNA vaccines, are gaining prominence. Notably, preclinical models often demonstrate superior outcomes compared to clinical trials, as results observed in animal models are not fully replicated in human studies. Conclusions: Despite challenges related to disease progression and patient loss, the studies reviewed highlight significant advancements in patient prognosis, emphasizing the potential of novel therapeutic vaccines as an effective alternative for the treatment of hematological cancers.
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Affiliation(s)
| | - Maria Gabriela Reis Carvalho
- Grupo de Informática de Biossistemas, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-002, Brazil;
- Biologia Computacional e Sistemas (BCS), Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil
| | - Jeronimo Conceição Ruiz
- Grupo de Informática de Biossistemas, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte 30190-002, Brazil;
- Biologia Computacional e Sistemas (BCS), Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil
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43
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Schoeberl B, Musante CJ, Ramanujan S. Future Directions for Quantitative Systems Pharmacology. Handb Exp Pharmacol 2025. [PMID: 39812657 DOI: 10.1007/164_2024_737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
In this chapter, we envision the future of Quantitative Systems Pharmacology (QSP) which integrates closely with emerging data and technologies including advanced analytics, novel experimental technologies, and diverse and larger datasets. Machine learning (ML) and Artificial Intelligence (AI) will increasingly help QSP modelers to find, prepare, integrate, and exploit larger and diverse datasets, as well as build, parameterize, and simulate models. We picture QSP models being applied during all stages of drug discovery and development: During the discovery stages, QSP models predict the early human experience of in silico compounds created by generative AI. In preclinical development, QSP will integrate with non-animal "new approach methodologies" and reverse-translated datasets to improve understanding of and translation to the human patient. During clinical development, integration with complementary modeling approaches and multimodal patient data will create multidimensional digital twins and virtual populations for clinical trial simulations that guide clinical development and point to opportunities for precision medicine. QSP can evolve into this future by (1) pursuing high-impact applications enabled by novel experimental and quantitative technologies and data types; (2) integrating closely with analytical and computational advancements; and (3) increasing efficiencies through automation, standardization, and model reuse. In this vision, the QSP expert will play a critical role in designing strategies, evaluating data, staging and executing analyses, verifying, interpreting, and communicating findings, and ensuring the ethical, safe, and rational application of novel data types, technologies, and advanced analytics including AI/ML.
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Wang B, Hasturk O, Kumarasinghe U, Rudolph S, Staii C, Chen Y, Kaplan DL. Temporary Nanoencapsulation of Human Intestinal Organoids Using Silk Ionomers. Adv Healthc Mater 2025; 14:e2403176. [PMID: 39648539 DOI: 10.1002/adhm.202403176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 11/03/2024] [Indexed: 12/10/2024]
Abstract
Human intestinal organoids (HIOs) are vital for modeling intestinal development, disease, and therapeutic tissue regeneration. However, their susceptibility to stress, immunological attack, and environmental fluctuations limits their utility in research and therapeutic applications. This study evaluated the effectiveness of temporary silk protein-based layer-by-layer (LbL) nanoencapsulation technique to enhance the viability and functions of HIOs against common biomedical stressors, without compromising their native functions. Cell viability and differentiation capacity are assessed, finding that nanoencapsulation significantly improved HIO survival under the various environmental perturbations studied without compromising cellular functionality. Post-stress exposures, the encapsulated HIOs still successfully differentiated into essential intestinal cell types such as enterocytes, goblet cells, enteroendocrine cells, and Paneth cells. Moreover, the silk nanocoatings effectively protected against environmental stressors such as ultraviolet (UV) light exposure, protease degradation, antibody binding, and cytokine-induced inflammation. This nanoencapsulation technique shows promise for advancing HIO applications in disease modeling, drug testing, and potential transplantation therapies.
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Affiliation(s)
- Brooke Wang
- Department of Biomedical Engineering, Tufts University, Medford, MA, USA
| | - Onur Hasturk
- Department of Biomedical Engineering, Tufts University, Medford, MA, USA
| | | | - Sara Rudolph
- Department of Biomedical Engineering, Tufts University, Medford, MA, USA
| | - Cristian Staii
- Department of Physics and Astronomy, Tufts University, Medford, MA, USA
| | - Ying Chen
- Department of Physics and Astronomy, Tufts University, Medford, MA, USA
| | - David L Kaplan
- Department of Physics and Astronomy, Tufts University, Medford, MA, USA
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Yildirim Z, Swanson K, Wu X, Zou J, Wu J. Next-Gen Therapeutics: Pioneering Drug Discovery with iPSCs, Genomics, AI, and Clinical Trials in a Dish. Annu Rev Pharmacol Toxicol 2025; 65:71-90. [PMID: 39284102 PMCID: PMC12011342 DOI: 10.1146/annurev-pharmtox-022724-095035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
In the high-stakes arena of drug discovery, the journey from bench to bedside is hindered by a daunting 92% failure rate, primarily due to unpredicted toxicities and inadequate therapeutic efficacy in clinical trials. The FDA Modernization Act 2.0 heralds a transformative approach, advocating for the integration of alternative methods to conventional animal testing, including cell-based assays that employ human induced pluripotent stem cell (iPSC)-derived organoids, and organ-on-a-chip technologies, in conjunction with sophisticated artificial intelligence (AI) methodologies. Our review explores the innovative capacity of iPSC-derived clinical trial in a dish models designed for cardiovascular disease research. We also highlight how integrating iPSC technology with AI can accelerate the identification of viable therapeutic candidates, streamline drug screening, and pave the way toward more personalized medicine. Through this, we provide a comprehensive overview of the current landscape and future implications of iPSC and AI applications being navigated by the research community and pharmaceutical industry.
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Affiliation(s)
- Zehra Yildirim
- Stanford Cardiovascular Institute and Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA;
| | - Kyle Swanson
- Greenstone Biosciences, Palo Alto, California, USA
- Department of Computer Science, Stanford University, Stanford, California, USA
| | - Xuekun Wu
- Stanford Cardiovascular Institute and Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA;
| | - James Zou
- Department of Computer Science, Stanford University, Stanford, California, USA
| | - Joseph Wu
- Stanford Cardiovascular Institute and Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA;
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46
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Ojeh N, Vecin NM, Pastar I, Volk SW, Wilgus T, Griffiths S, Ramey‐Ward AN, Driver VR, DiPietro LA, Gould LJ, Tomic‐Canic M. The Wound Reporting in Animal and Human Preclinical Studies (WRAHPS) Guidelines. Wound Repair Regen 2025; 33:e13232. [PMID: 39639458 PMCID: PMC11621255 DOI: 10.1111/wrr.13232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 10/02/2024] [Accepted: 10/28/2024] [Indexed: 12/07/2024]
Abstract
Preclinical studies for wound healing disorders are an essential step in translating discoveries into therapies. Also, they are an integral component of initial safety screening and gaining mechanistic insights using an in vivo approach. Given the complexity of the wound healing process, existing guidelines for animal testing do not capture key information due to the inevitable variability in experimental design. Variations in study interpretation are increased by complexities associated with wound aetiology, wounding procedure, multiple treatment conditions, wound assessment, and analysis, as well as lack of acknowledgement of limitation of the model used. Yet, no standards exist to guide reporting crucial experimental information required to interpret results in translational studies of wound healing. Consistency in reporting allows transparency, comparative, and meta-analysis studies and avoids repetition and redundancy. Therefore, there is a critical and unmet need to standardise reporting for preclinical wound studies. To aid in reporting experimental conditions, The Wound Reporting in Animal and Human Preclinical Studies (WRAHPS) Guidelines have now been created by the authors working with the Wound Care Collaborative Community (WCCC) GAPS group to provide a checklist and reporting template for the most frequently used preclinical models in support of development for human clinical trials for wound healing disorders. It is anticipated that the WRAHPS Guidelines will standardise comprehensive methods for reporting in scientific manuscripts and the wound healing field overall. This article is not intended to address regulatory requirements but is intended to provide general guidelines on important scientific considerations for such studies.
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Affiliation(s)
- Nkemcho Ojeh
- Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiFloridaUSA
- Department of Preclinical and Health Sciences, Faculty of Medical SciencesThe University of the West IndiesBridgetownBarbados
| | - Nicole M. Vecin
- Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiFloridaUSA
| | - Irena Pastar
- Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiFloridaUSA
| | - Susan W. Volk
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Traci Wilgus
- Department of PathologyThe Ohio State UniversityColumbusOhioUSA
| | | | | | - Vickie R. Driver
- School of MedicineWashington State UniversitySpokaneWashingtonUSA
| | - Luisa A. DiPietro
- Center for Wound Healing and Tissue RegenerationUniversity of Illinois ChicagoChicagoIllinoisUSA
| | - Lisa J. Gould
- South Shore Hospital Center for Wound HealingWeymouthMassachusettsUSA
| | - Marjana Tomic‐Canic
- Wound Healing and Regenerative Medicine Research Program, Dr Phillip Frost Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiFloridaUSA
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47
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Coll RC, Schroder K. Inflammasome components as new therapeutic targets in inflammatory disease. Nat Rev Immunol 2025; 25:22-41. [PMID: 39251813 DOI: 10.1038/s41577-024-01075-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 09/11/2024]
Abstract
Inflammation drives pathology in many human diseases for which there are no disease-modifying drugs. Inflammasomes are signalling platforms that can induce pathological inflammation and tissue damage, having potential as an exciting new class of drug targets. Small-molecule inhibitors of the NLRP3 inflammasome that are now in clinical trials have demonstrated proof of concept that inflammasomes are druggable, and so drug development programmes are now focusing on other key inflammasome molecules. In this Review, we describe the potential of inflammasome components as candidate drug targets and the novel inflammasome inhibitors that are being developed. We discuss how the signalling biology of inflammasomes offers mechanistic insights for therapeutic targeting. We also discuss the major scientific and technical challenges associated with drugging these molecules during preclinical development and clinical trials.
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Affiliation(s)
- Rebecca C Coll
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
| | - Kate Schroder
- Institute for Molecular Bioscience (IMB), The University of Queensland, St Lucia, Queensland, Australia.
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Gregory DJ, Han F, Li P, Gritsenko MA, Kyle J, Riley FE, Chavez D, Yotova V, Sindeaux RHM, Hawash MBF, Xu F, Hung LY, Hayden DL, Tompkins RG, Lanford RE, Kobzik L, Hellman J, Jacobs JM, Barreiro LB, Xiao W, Warren HS. Molecular profiles of blood from numerous species that differ in sensitivity to acute inflammation. Mol Med 2024; 30:280. [PMID: 39730996 DOI: 10.1186/s10020-024-01052-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 12/18/2024] [Indexed: 12/29/2024] Open
Abstract
Vertebrates differ over 100,000-fold in responses to pro-inflammatory agonists such as bacterial lipopolysaccharide (LPS), complicating use of animal models to study human sepsis or inflammatory disorders. We compared transcriptomes of resting and LPS-exposed blood from six LPS-sensitive species (rabbit, pig, sheep, cow, chimpanzee, human) and four LPS-resilient species (mice, rats, baboon, rhesus), as well as plasma proteomes and lipidomes. Unexpectedly, at baseline, sensitive species already had enhanced expression of LPS-responsive genes relative to resilient species. After LPS stimulation, maximally different genes in resilient species included genes that detoxify LPS, diminish bacterial growth, discriminate sepsis from SIRS, and play roles in autophagy and apoptosis. The findings reveal the molecular landscape of species differences in inflammation. This may inform better selection of species for pre-clinical models and could lead to new therapeutic strategies that mimic mechanisms in inflammation-resilient species to limit inflammation without causing immunosuppression.
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Affiliation(s)
- David J Gregory
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Feifei Han
- Harvard Medical School, Boston, MA, USA
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Peng Li
- Harvard Medical School, Boston, MA, USA
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Marina A Gritsenko
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Jennifer Kyle
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Frank E Riley
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA
| | - Deborah Chavez
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Vania Yotova
- Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
| | | | - Mohamed B F Hawash
- Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
- Department of Biochemistry, University of Montréal, Montréal, QC, Canada
- Hospital for Sick Children, Toronto, Canada
| | - Fengyun Xu
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA
| | - Li-Yuan Hung
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Douglas L Hayden
- Harvard Medical School, Boston, MA, USA
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ronald G Tompkins
- Harvard Medical School, Boston, MA, USA
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Robert E Lanford
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Lester Kobzik
- Program in Molecular and Integrative Physiological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Judith Hellman
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA
| | - Jon M Jacobs
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Luis B Barreiro
- Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada
- Department of Biochemistry, University of Montréal, Montréal, QC, Canada
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA
- Department of Human Genetics, University of Chicago, Chicago, IL, USA
- Committee On Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA
- Committee On Immunology, University of Chicago, Chicago, IL, USA
| | - Wenzhong Xiao
- Harvard Medical School, Boston, MA, USA.
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
| | - H Shaw Warren
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
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Jamiyansharav M, Shin H, Kim B, Kim H, Han SJ, Seong JK, Suh JG, Seo KY. Characteristic visual phenotypes in Korean wild mice (KWM/Hym). Lab Anim Res 2024; 40:42. [PMID: 39716311 DOI: 10.1186/s42826-024-00230-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 11/11/2024] [Accepted: 11/21/2024] [Indexed: 12/25/2024] Open
Abstract
BACKGROUND In the last few decades, numerous efforts have been made to develop a better mouse model to overcome the current limitations of laboratory inbred mouse models such as have a weaker and simpler immune status. As part of these efforts, in Korea, the Hallym university medical genetics research team has been developing a new inbred strain of Korean wild mouse KWM/Hym. It was suggested that this strain, which is derived from wild mice, might be useful for genetic research and may become a valuable tool for overcoming some limitations seen in inbred mice that are currently used in the laboratory. Furthermore, for this study, we aimed to determine the visual phenotype of this unique strain KWM/Hym, and consider whether and if they are suitable for visual research. To analyze their visual phenotype, we performed the functional and morphological examinations in KWM/Hym mice and compared the results with laboratory mice which are the most common background strain. RESULTS KWM/Hym had a thin corneal phenotype, thin but well-ordered retina due to their light body weight characteristic, and normal visual function similar to control mice. Unexpectedly, the KWM/Hym mice developed cataracts only at around 25 weeks old. CONCLUSIONS We suggest Korean wild mouse KWM/Hym is useful for visual experiments and could be an animal model of eye disease in humans.
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Affiliation(s)
- Munkhdelger Jamiyansharav
- Department of Ophthalmology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Haesol Shin
- Department of Ophthalmology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Korea Mouse Sensory Phenotyping Center (KMSPC), Yonsei University College of Medicine, Seoul, Korea
| | - Boyoung Kim
- Department of Medical Genetics, College of Medicine, Hallym University, 1, Hallymdaehak-gil, Chuncheon-si, 24252, Gangwon-do, Republic of Korea
| | - Hongkyung Kim
- Korea Mouse Sensory Phenotyping Center (KMSPC), Yonsei University College of Medicine, Seoul, Korea
| | - Soo Jung Han
- Department of Ophthalmology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Je Kyung Seong
- Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, and Korea Mouse Phenotyping Center, Seoul National University, Seoul, Korea
| | - Jun Gyo Suh
- Department of Medical Genetics, College of Medicine, Hallym University, 1, Hallymdaehak-gil, Chuncheon-si, 24252, Gangwon-do, Republic of Korea.
| | - Kyoung Yul Seo
- Department of Ophthalmology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
- Korea Mouse Sensory Phenotyping Center (KMSPC), Yonsei University College of Medicine, Seoul, Korea.
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Fuadah Y, Pramudito MA, Firdaus L, Vanheusden FJ, Lim KM. QSAR Classification Modeling Using Machine Learning with a Consensus-Based Approach for Multivariate Chemical Hazard End Points. ACS OMEGA 2024; 9:50796-50808. [PMID: 39741811 PMCID: PMC11683616 DOI: 10.1021/acsomega.4c09356] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/15/2024] [Accepted: 12/03/2024] [Indexed: 01/03/2025]
Abstract
This study introduces an innovative computational approach using hybrid machine learning models to predict toxicity across eight critical end points: cardiac toxicity, inhalation toxicity, dermal toxicity, oral toxicity, skin irritation, skin sensitization, eye irritation, and respiratory irritation. Leveraging advanced cheminformatics tools, we extracted relevant features from curated data sets, incorporating a range of descriptors such as Morgan circular fingerprints, MACCS keys, Mordred calculation descriptors, and physicochemical properties. The consensus model was developed by selecting the best-performing classifier-Random Forest (RF), eXtreme Gradient Boosting (XGBoost), or Support Vector Machines (SVM)-for each descriptor, optimizing predictive accuracy and robustness across the end points. The model obtained strong predictive performance, with area under the curve (AUC) scores ranging from 0.78 to 0.90. This framework offers a reliable, ethical, and effective in silico approach to chemical safety assessment, underscoring the potential of advanced computational methods to support both regulatory and research applications in toxicity prediction.
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Affiliation(s)
- Yunendah
Nur Fuadah
- Computational
Medicine Lab, Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi 39177, Republic of Korea
- School
of Electrical Engineering, Telkom University, Bandung 40257, Indonesia
| | - Muhammad Adnan Pramudito
- Computational
Medicine Lab, Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi 39177, Republic of Korea
| | - Lulu Firdaus
- Computational
Medicine Lab, Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi 39177, Republic of Korea
| | - Frederique J. Vanheusden
- Department
of Engineering, School of Science and Technology, Nottingham Trent University, New Hall Block, Room 177, Clifton Campus, Clifton
Lane, Nottingham NG11 8NS, U.K.
| | - Ki Moo Lim
- Computational
Medicine Lab, Department of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi 39177, Republic of Korea
- Computational
Medicine Lab, Department of Medical IT Convergence Engineering, Kumoh National Institute of Technology, Gumi 39177, Republic of Korea
- Meta
Heart Co., Ltd., Gumi 39253, Republic of Korea
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