Journal of Immunotoxicology最新文献

{"title":"An overview of immune safety avatar: mimicking the effects of immunomodulatory therapies on the immune system.","authors":"Vanessa Neuhaus, Laure-Alix Clerbaux, Katherina Sewald","doi":"10.1080/1547691X.2024.2354213","DOIUrl":"https://doi.org/10.1080/1547691X.2024.2354213","url":null,"abstract":"<p><p>Innovative therapeutics like biologicals that modulate the immune system are on the rise. However, their immune-modulating characteristics can also lead sometimes to the induction of adverse effects, by triggering unintended immune reactions. Due to the complexity and target-specificity of such therapeutics, these drug-induced adverse events could remain undetected during non-clinical development, if the test systems are, for example, animal-based, and only emerge in clinical development when tested in humans and subsequently lead to discontinuance of otherwise promising drug candidates. To identify adverse effects on the human immune system at an early stage, new approaches, assays, and technologies are needed. The Innovative Medicine Initiative (IMI) cooperation Immune Safety Avatar (imSAVAR) project aims to develop a tool for integrated non-clinical safety assessment for immune-modulatory new therapeutic drugs and clinical trial applications. To achieve this goal, imSAVAR has relied on the Adverse Outcome Pathway (AOP) framework to gather knowledge in a structured approach and to design, select or develop, when needed, appropriate test systems for prediction of the immune-related adverse outcomes. So far, the imSAVAR consortium has identified the \"mode of action\" for certain classes of drugs that needed improved risk assessment, including chimeric antigen receptor T cells (CAR T cells), immune checkpoint inhibitors (ICIs), and recombinant proteins (e.g. interleukin [IL]-2), has linked those to their immune-related adverse outcomes and has formulated literature-based immune-related AOPs (irAOPs). Models to measure those immune-specific perturbations were selected, adjusted, or newly developed. The imSAVAR work described in this special issue of <i>The Journal of Immunotoxicology</i> supports our understanding of immune-mediated adverse effects and their early discovery during development to improve the safety of innovative biomedicals.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"21 sup1","pages":"S1-S4"},"PeriodicalIF":2.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analyzing IL-2-induced vascular leakage with an irAOP as tool.","authors":"Patricia Gogesch, Samira Ortega Iannazzo, Tamara Zimmermann, Remi Villenave, Katherina Sewald, Zoe Waibler","doi":"10.1080/1547691X.2024.2369123","DOIUrl":"https://doi.org/10.1080/1547691X.2024.2369123","url":null,"abstract":"<p><p>Immune-related adverse outcome pathways (irAOPs) are a toxicological tool for the structuring of complex immunological mechanisms. The EU-funded IMI-project imSAVAR analyses the applicability of irAOPs in pre-clinical safety assessment of immunotherapies. Here, we use immunotherapy with interleukin (IL)-2 as a use case to develop an irAOP for IL-2-mediated vascular leakage (VL). Despite severe side effects observed upon high-dose treatment, IL-2 remains a promising candidate for cancer- and autoimmune therapy. The secondary systemic capillary leakage syndrome is described by a high mortality and a lethality rate of 20 - 30%. However, due to its non-specific symptoms, it remains a serious but under-diagnosed pathology. VL as general phenomenon is associated with several pro-inflammatory scenarios or observed as severe side effect of immunotherapies. In such situations, the physiological condition, in which endothelial cells (ECs) form the semipermeable seal of the vasculature, can escalate into pathological vascular permeability and finally VL. Although EC-biology and mechanisms underlying VL are ongoing subjects of research since many years, exact understanding of VL pathophysiology remains unclear. With this review, we provide an overview of the development of VL from an immunological perspective in the context of high-dose IL-2 immunotherapy. We structured the corresponding knowledge and generated an irAOP for IL-2-mediated VL with the aim to identify gaps and possible biomarkers. Gained insights from this theoretical approach facilitate the identification of relevant scientific questions as a basis for concrete experimental work. Integration of novel experiment-based knowledge into the existing irAOP could close a 'feedback-loop' by enabling irAOP-refinement and the identification of new questions. At the same time this could give rise to important information to improve test systems for IL-2-based immunotherapy safety-assessment and overall the approach to understand, prevent, or predict VL as critical side effect of other clinical conditions.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"21 sup1","pages":"S79-S88"},"PeriodicalIF":2.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revival of recombinant IL-2 therapy - approaches from the past until today.","authors":"Luise A Roser, Charline Sommer, Samira Ortega Iannazzo, Christina Sakellariou, Zoe Waibler, Patricia Gogesch","doi":"10.1080/1547691X.2024.2335219","DOIUrl":"10.1080/1547691X.2024.2335219","url":null,"abstract":"<p><p>Interleukin-2 (IL-2) was one of the first cytokines discovered and its central role in T cell function soon led to the notion that the cytokine could specifically activate immune cells to combat cancer cells. Recombinant human IL-2 (recIL-2) belonged to the first anti-cancer immunotherapeutics that received marketing authorization and while it mediated anti-tumor effects in some cancer entities, treatment was associated with severe and systemic side effects. RecIL-2 holds an exceptional therapeutic potential, which can either lead to stimulation of the immune system - favorable during cancer treatment - or immunosuppression - used for treatment of inflammatory diseases such as autoimmunity. Due to these pleiotropic immune effects, recIL-2 therapy is still a hot topic in research and modified recIL-2 drug candidates show ameliorated efficacy and safety in pre-clinical and clinical studies. The Immune Safety Avatar (imSAVAR) consortium aims to systemically assess mechanisms leading to adverse events provoked by recIL-2 immunotherapy as a use case in order to aid safety evaluation of future recIL-2-based therapies. Here, we summarize the historical use of recIL-2 therapy, associated side effects, and describe the molecular basis of the dual role of IL-2. Finally, an overview of new recIL-2 compounds and delivery systems, which are currently being developed, will be given, highlighting a possible comeback of recIL-2 therapy.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"21 sup1","pages":"S38-S47"},"PeriodicalIF":2.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying CD19-targeted CAR-T cell immune pathways in an in vitro human immune mimetic cytokine release assay.","authors":"Thuvan Dinh-Le, John Escobar, Louis Poisson, Karissa Adkins, Maria Jornet Culubret, Lukas Scheller, Jan van den Brulle, Michael Hudecek, Donald R Drake Iii, Miriam Alb, Ernesto Luna","doi":"10.1080/1547691X.2024.2378729","DOIUrl":"https://doi.org/10.1080/1547691X.2024.2378729","url":null,"abstract":"<p><p>CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells have shown success in clinical studies, with several CD19 CAR-T cell products now having been approved for market use. However, this cell therapy can be associated with side effects such as cytokine release syndrome (CRS). Therefore, pre-clinical test systems are highly desired to permit the evaluation of these unwanted effects before clinical trials begin. In this study, we evaluated cytokine secretion and cell phenotype changes induced by human CD4⁺ and CD8⁺ CD19-targeted CAR-T cells in the cytokine release assay (CRA) module of a pre-clinical human <i>in vitro</i> 3D co-culture platform. The <i>in vitro</i> CRA data showed that CD19-targeted CAR-T cells induced a diverse and concentration-dependent cytokine response led by a T_H1-profile (IFNγ, IL-2) and pro-inflammatory cytokines (IL-6, TNFα, MCP-1, IL-8, MIP-1b). It was also shown that different cellular components in this 3D co-culture system contributed to the CAR-T cell cytokine response. In particular, whole blood-derived cell populations were necessary to drive the production of T cell cytokines, and endothelial cells were required to generate pro-inflammatory cytokines. CD19-targeted CAR-T cells also triggered cell phenotype changes, including the activation of whole blood-derived CD4⁺ and CD8⁺ T-cells and activation/maturation of antigen-presenting cells, during treatment of the <i>in vitro</i> CRA platform. Additionally, the observation of a CD19-targeted CAR-T cell concentration-dependent reduction in the B-cell compartment in this study is aligned with the expected pharmacology and clinical profile of this compound. Overall, this dataset shows the utility of an <i>in vitro</i> CRA model as a pre-clinical platform for evaluating cytokine release potential and analysis of mechanisms of action of CD19-targeted CAR-T cells.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"21 sup1","pages":"S29-S37"},"PeriodicalIF":2.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel strategies to assess cytokine release mediated by chimeric antigen receptor T cells based on the adverse outcome pathway concept.","authors":"Miriam Alb, Kristin Reiche, Michael Rade, Katherina Sewald, Peter Loskill, Madalena Cipriano, Tengku Ibrahim Maulana, Andries D van der Meer, Huub J Weener, Laure-Alix Clerbaux, Birgit Fogal, Nirav Patel, Karissa Adkins, Emma Lund, Ethan Perkins, Christopher Cooper, Jan van den Brulle, Hannah Morgan, Tina Rubic-Schneider, Hui Ling, Keith DiPetrillo, Jonathan Moggs, Ulrike Köhl, Michael Hudecek","doi":"10.1080/1547691X.2024.2345158","DOIUrl":"10.1080/1547691X.2024.2345158","url":null,"abstract":"<p><p>The success of cellular immunotherapies such as chimeric antigen receptor (CAR) T cell therapy has led to their implementation as a revolutionary treatment option for cancer patients. However, the safe translation of such novel immunotherapies, from non-clinical assessment to first-in-human studies is still hampered by the lack of suitable <i>in vitro</i> and <i>in vivo</i> models recapitulating the complexity of the human immune system. Additionally, using cells derived from human healthy volunteers in such test systems may not adequately reflect the altered state of the patient's immune system thus potentially underestimating the risk of life-threatening conditions, such as cytokine release syndrome (CRS) following CAR T cell therapy. The IMI2/EU project imSAVAR (immune safety avatar: non-clinical mimicking of the immune system effects of immunomodulatory therapies) aims at creating a platform for novel tools and models for enhanced non-clinical prediction of possible adverse events associated with immunomodulatory therapies. This platform shall in the future guide early non-clinical safety assessment of novel immune therapeutics thereby also reducing the costs of their development. Therefore, we review current opportunities and challenges associated with non-clinical <i>in vitro</i> and <i>in vivo</i> models for the safety assessment of CAR T cell therapy ranging from organ-on-chip models up to advanced biomarker screening.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"21 sup1","pages":"S13-S28"},"PeriodicalIF":2.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-2-mediated hepatotoxicity: knowledge gap identification based on the irAOP concept","authors":"Luise A. Roser, Christina Sakellariou, Malin Lindstedt, Vanessa Neuhaus, Susann Dehmel, Charline Sommer, Martin Raasch, Thierry Flandre, Sigrid Roesener, Philip Hewitt, Michael J. Parnham, Katherina Sewald, Susanne Schiffmann","doi":"10.1080/1547691x.2024.2332177","DOIUrl":"https://doi.org/10.1080/1547691x.2024.2332177","url":null,"abstract":"Drug-induced hepatotoxicity constitutes a major reason for non-approval and post-marketing withdrawal of pharmaceuticals. In many cases, preclinical models lack predictive capacity for hepatic dama...","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"107 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140560865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fine tuning of the innate and adaptive immune responses by Interleukin-2.","authors":"Christina Sakellariou, Luise A Roser, Susanne Schiffmann, Malin Lindstedt","doi":"10.1080/1547691X.2024.2332175","DOIUrl":"10.1080/1547691X.2024.2332175","url":null,"abstract":"<p><p>Novel immunotherapies for cancer and other diseases aim to trigger the immune system to produce durable responses, while overcoming the immunosuppression that may contribute to disease severity, and in parallel considering immunosafety aspects. Interleukin-2 (IL-2) was one of the first cytokines that the FDA approved as a cancer-targeting immunotherapy. However, in the past years, IL-2 immunotherapy is not actively offered to patients, due to limited efficacy, when compared to other novel immunotherapies, and the associated severe adverse events. In order to design improved <i>in vitro</i> and <i>in vivo models</i>, able to predict the efficacy and safety of novel IL-2 alternatives, it is important to delineate the mechanistic immunological events triggered by IL-2. Particularly, in this review we will discuss the effects IL-2 has with the bridging cell type of the innate and adaptive immune responses, dendritic cells. The pathways involved in the regulation of IL-2 by dendritic cells and T-cells in cancer and autoimmune disease will also be explored.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"21 1","pages":"2332175"},"PeriodicalIF":3.3,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to the anti-microbial chemical triclosan disrupts keratinocyte function and skin integrity in a model of reconstructed human epidermis.","authors":"Rachel Baur, Michael Kashon, Ewa Lukomska, Lisa M Weatherly, Hillary L Shane, Stacey E Anderson","doi":"10.1080/1547691X.2022.2148781","DOIUrl":"10.1080/1547691X.2022.2148781","url":null,"abstract":"<p><p>Triclosan is an anti-microbial chemical incorporated into products that are applied to the skin of healthcare workers. Exposure to triclosan has previously been shown to be associated with allergic disease in humans and impact the immune responses in animal models. Additionally, studies have shown that exposure to triclosan dermally activates the NLRP3 inflammasome and disrupts the skin barrier integrity in mice. The skin is the largest organ of the body and plays an important role as a physical barrier and regulator of the immune system. Alterations in the barrier and immune regulatory functions of the skin have been demonstrated to increase the risk of sensitization and development of allergic disease. In this study, the impact of triclosan exposure on the skin barrier and keratinocyte function was investigated using a model of reconstructed human epidermis. The apical surface of reconstructed human epidermis was exposed to triclosan (0.05-0.2%) once for 6, 24, or 48 h or daily for 5 consecutive days. Exposure to triclosan increased epidermal permeability and altered the expression of genes involved in formation of the skin barrier. Additionally, exposure to triclosan altered the expression patterns of several cytokines and growth factors. Together, these results suggest that exposure to triclosan impacts skin barrier integrity and function of human keratinocytes and suggests that these alterations may impact immune regulation.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"20 1","pages":"1-11"},"PeriodicalIF":2.4,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10364087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10255699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of epithelial-specific MyD88 signaling pathway on airway inflammatory response to organic dust exposure.","authors":"Amber N Johnson, John Dickinson, Amy Nelson, Rohit Gaurav, Katrina Kudrna, Scott E Evans, Katherine Janike, Todd A Wyatt, Jill A Poole","doi":"10.1080/1547691X.2022.2148782","DOIUrl":"10.1080/1547691X.2022.2148782","url":null,"abstract":"<p><p>The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE <i>in vivo</i>, the surfactant protein C protein (SPC) Cre⁺ embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre⁺, MyD88 floxed, were also developed. Using an established protocol, mice were intranasally instilled with ODE or saline once or daily up to 3 weeks. Mice with MyD88-deficient SPC⁺ lung epithelial cells exhibited decreased neutrophil influx following ODE exposure once and repetitively for 1 week without modulation of classic pro-inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and neutrophil chemoattractants. This protective response was lost after 3 weeks of repetitive exposure. ODE-induced Muc5ac mucin expression at 1 week was also reduced in MyD88-deficient SPC⁺ cells. Acute ODE-induced IL-33 was reduced in MyD88-deficient SPC⁺ cells whereas serum IgE levels were increased at one week. In contrast, mice with inducible MyD88-deficient CCSP⁺ airway epithelial cells demonstrated no significant difference in experimental indices following ODE exposure. Collectively, these findings suggest that MyD88-dependent signaling targeted to all airway epithelial cells plays an important role in mediating neutrophil influx and mucin production in response to acute organic dust exposures.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"20 1","pages":"2148782"},"PeriodicalIF":2.4,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9912912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9294632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Legacy and emerging per- and polyfluoroalkyl substances suppress the neutrophil respiratory burst.","authors":"Drake W Phelps, Anika I Palekar, Haleigh E Conley, Giuliano Ferrero, Jacob H Driggers, Keith E Linder, Seth W Kullman, David M Reif, M Katie Sheats, Jamie C DeWitt, Jeffrey A Yoder","doi":"10.1080/1547691X.2023.2176953","DOIUrl":"10.1080/1547691X.2023.2176953","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFASs) are used in a multitude of processes and products, including nonstick coatings, food wrappers, and fire-fighting foams. These chemicals are environmentally-persistent, ubiquitous, and can be detected in the serum of 98% of Americans. Despite evidence that PFASs alter adaptive immunity, few studies have investigated their effects on innate immunity. The report here presents results of studies that investigated the impact of nine environmentally-relevant PFASs [e.g. perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid potassium salt (PFOS-K), perfluorononanoic acid (PFNA), perfluorohexanoic acid (PFHxA), perfluorohexane sulfonic acid (PFHxS), perfluorobutane sulfonic acid (PFBS), ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX), 7H-perfluoro-4-methyl-3,6-dioxa-octane sulfonic acid (Nafion byproduct 2), and perfluoromethoxyacetic acid sodium salt (PFMOAA-Na)] on one component of the innate immune response, the neutrophil respiratory burst. The respiratory burst is a key innate immune process by which microbicidal reactive oxygen species (ROS) are rapidly induced by neutrophils in response to pathogens; defects in the respiratory burst can increase susceptibility to infection. The study here utilized larval zebrafish, a human neutrophil-like cell line, and primary human neutrophils to ascertain whether PFAS exposure inhibits ROS production in the respiratory burst. It was observed that exposure to PFHxA and GenX suppresses the respiratory burst in zebrafish larvae and a human neutrophil-like cell line. GenX also suppressed the respiratory burst in primary human neutrophils. This report is the first to demonstrate that these PFASs suppress neutrophil function and support the utility of employing zebrafish larvae and a human cell line as screening tools to identify chemicals that may suppress human immune function.</p>","PeriodicalId":16073,"journal":{"name":"Journal of Immunotoxicology","volume":"20 1","pages":"2176953"},"PeriodicalIF":2.4,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9852039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}