American Journal of Pathology最新文献

{"title":"Interplay between Leptin and Stearoyl-CoA Desaturase 1 in Estrogen Receptor-Positive Breast Cancer Cells.","authors":"Felice Maria Accattatis, Luca Gelsomino, Linda Manna, Piercarlo Del Console, Laura Bianchi, Alfonso Carleo, Rossana De Salvo, Lorenzo Arnaboldi, Ludovica Baù, Alberto Corsini, Adele Elisabetta Leonetti, Rocco Malivindi, Marco Fiorillo, Michael P Lisanti, Cinzia Giordano, Daniela Bonofiglio, Sebastiano Andò, Stefania Catalano, Ines Barone","doi":"10.1016/j.ajpath.2025.08.009","DOIUrl":"10.1016/j.ajpath.2025.08.009","url":null,"abstract":"<p><p>Obesity, a global health challenge, contributes to various cancers, including breast cancer. Complex metabolic dysregulation marks the development of both breast cancer and obesity. Here, the interplay between the obesity-derived adipokine leptin (LEP) and stearoyl-CoA desaturase 1 (SCD), a critical enzyme in fatty acid (FA) metabolism, was explored. STRING database analysis reported a significant protein-protein interaction between LEP and SCD. Functional processing of the differentially expressed genes in LEP-treated breast cancer cells revealed a critical involvement of SCD in the interactome of differentially expressed gene-coding proteins. Kaplan-Meier analyses linked LEP/SCD expression to poorer recurrence-free survival in patients with estrogen receptor α luminal A-like breast cancer. Functional studies demonstrated that LEP up-regulated SCD expression in luminal A-like breast cancer cells through LEP receptor-mediated signaling and activation of sterol regulatory element-binding-protein-1 (SREBP1), a key transcription factor modulating SCD gene transcription. Lipidomic profiling showed that SCD inhibition using MF-438 reduced LEP-induced FA desaturation, characterized by a shift from saturated to monounsaturated FAs. SCD inhibition also abolished the LEP-mediated mitochondrial respiration and ATP production. Additionally, LEP-induced oncogenic features, including enhanced growth and motility, were counteracted by pharmacologic/genetic SCD blockade, confirming SCD's role in leptin's protumorigenic effects. This study highlights the LEP-SCD axis as a driver of metabolic and functional alterations in estrogen receptor α-positive breast cancer, providing insights into the obesity-breast cancer link and identifying potential therapeutic targets (ie, SCD) to counter obesity-driven breast cancer progression.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-Modality Learning for Predicting Immunohistochemistry Biomarkers from Hematoxylin and Eosin-Stained Whole Slide Images.","authors":"Amit Das, Naofumi Tomita, Kyle J Syme, Weijie Ma, Paige O'Connor, Kristin N Corbett, Bing Ren, Xiaoying Liu, Saeed Hassanpour","doi":"10.1016/j.ajpath.2025.08.014","DOIUrl":"10.1016/j.ajpath.2025.08.014","url":null,"abstract":"<p><p>Hematoxylin and eosin (H&E) staining is a cornerstone of pathologic analysis, offering reliable visualization of cellular morphology and tissue architecture for cancer diagnosis, subtyping, and grading. Immunohistochemistry (IHC) staining provides insights by detecting specific proteins within tissues, enhancing diagnostic accuracy, and improving treatment planning. However, IHC staining is costly, time-consuming, and resource intensive, requiring specialized expertise. To address these limitations, this study proposes HistoStainAlign, a novel deep learning framework that predicts IHC staining patterns directly from H&E whole slide images. The framework integrates paired H&E and IHC embeddings through a contrastive training strategy, capturing complementary features across staining modalities without patch-level annotations or tissue registration. The model was evaluated on gastrointestinal and lung tissue whole slide images with three commonly used IHC stains: P53, programmed death ligand-1, and Ki-67. HistoStainAlign achieved weighted F1 scores of 0.735 (95% CI, 0.670-0.799), 0.830 (95% CI, 0.772-0.886), and 0.723 (95% CI, 0.607-0.836), respectively for these three IHC stains. Embedding analyses demonstrated the robustness of the contrastive alignment in capturing meaningful cross-stain relationships. Comparisons with a baseline model further highlight the advantage of incorporating contrastive learning for improved stain pattern prediction. This study demonstrates the potential of computational approaches to serve as a prescreening tool, helping prioritize cases for IHC staining and improving workflow efficiency.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of PD-L1 in Regulatory T Cell-Mediated Suppression of Corneal Neovascularization.","authors":"Shima Dehghani, Manuel Chacon, Katayoon Forouzanfar, Seokjoo Lee, Akitomo Narimatsu, Rohan Bir Singh, Aytan Musayeva, Francesca Kahale, Sonia Anchouche, Neda Heydarian, Shilpy Bhullar, Thomas H Dohlman, Yihe Chen, Tomas Blanco, Reza Dana","doi":"10.1016/j.ajpath.2025.08.008","DOIUrl":"10.1016/j.ajpath.2025.08.008","url":null,"abstract":"<p><p>Corneal neovascularization (NV) leads to inflammation and fibrosis, thereby compromising visual acuity and corneal graft survival. Despite existing antiangiogenic therapies, clinical outcomes remain suboptimal. This study explores the antiangiogenic potential of regulatory T cells (Tregs) through programmed death-ligand 1 (PD-L1). In vitro tube formation assays were performed by co-culturing MS1 endothelial cells with Tregs. In addition, murine corneal suture-induced NV and high-risk corneal transplantation models were used to evaluate the effects of subconjunctival Treg injections in vivo. Wild-type (WT) Tregs inhibited endothelial tube formation, whereas PD-L1^-/- Tregs failed to exert this effect. Blocking B7-1 on MS1 cells attenuated the inhibitory effect of WT Tregs, indicating a PD-L1-B7-1 interaction as a key mechanism. Furthermore, vascular endothelial growth factor A expression in MS1 cells was significantly reduced on co-culturing with WT Tregs, a response that was absent with PD-L1^-/- Tregs. In vivo, subconjunctival Treg injections significantly reduced corneal NV in both corneal suture-induced NV and high-risk corneal transplantation models, and this effect was lost on blocking PD-L1. These results show that PD-L1 expressed by Tregs plays a pivotal role in suppressing corneal angiogenesis, acting through a contact-dependent mechanism through B7-1, leading to down-regulation of vascular endothelial growth factor A, highlighting the function of PD-L1 in Treg modulation of corneal angiogenesis.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SCG2 Transcriptionally Activated by SP1 Promotes Nasal Epithelial Cell Proliferation and Epithelial Mesenchymal Transition.","authors":"Jiabin Zhan, Quan Qiu, Zhengling Chen, Xin Wei, Xi Chen, Jing Zheng","doi":"10.1016/j.ajpath.2025.07.016","DOIUrl":"10.1016/j.ajpath.2025.07.016","url":null,"abstract":"<p><p>Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a tendency to recur and a poor prognosis; epithelial mesenchymal transition (EMT) and proliferation of nasal epithelial cells (NECs) play an important role in CRSwNP development. Secretogranin II (SCG2) is reported to be an EMT-related gene, but its role in CRSwNP has not been reported. In this study, human NECs were cultured in an air-liquid interface culture system and stimulated with IL-13 to maintain or promote the CRSwNP state. EMT-associated protein expression levels were examined by real-time quantitative PCR and Western blot. Dual luciferase, chromatin immunoprecipitation, and co-immunoprecipitation experiments were used to validate the regulatory relationship between SP1, SCG2, and UBQLN1. The nuclear translocation of Snail was examined by immunofluorescence assay. The results showed that the expression levels of SP1, SCG2, and UBQLN1 were all up-regulated in CRSwNP tissues. SCG2 knockdown inhibited EMT and proliferation of human NECs. Mechanistically, SP1 promoted the proliferation and EMT of human NECs by transcriptionally increasing SCG2 expression. SCG2 activated the AKT/GSK-3β/Snail pathway and promoted Snail nuclear translocation via UBQLN1. In short, SCG2, which is transcriptionally up-regulated by SP1, promotes the proliferation and EMT of human NECs by activating the AKT/GSK-3β/Snail pathway through binding to UBQLN1.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Growth Differentiation Factor 11 Attenuates Photoaging through Ferroptosis Pathway in SZ95 Sebocytes.","authors":"Ying Liu, Jingran Zeng, Xueyi Liu, Youyou Qin, Yingbo Zhang, Christos C Zouboulis, Zhibo Xiao","doi":"10.1016/j.ajpath.2025.07.015","DOIUrl":"10.1016/j.ajpath.2025.07.015","url":null,"abstract":"<p><p>Sebaceous glands synthesize and secrete sebum, forming a protective barrier on the skin. However, prolonged exposure to UV radiation leads to glandular atrophy and reduced sebum production. This study investigated the impact of UVB irradiation on sebocyte function and demonstrated that growth differentiation factor (GDF)-11 can attenuate UVB-induced damage. The findings indicate that cumulative UVB irradiation induces photoaging in sebocytes, characterized by impaired cellular function and up-regulation of cellular senescence markers, along with reduced GDF11 expression. Notably, GDF11 overexpression alleviated these adverse effects. Apoptosis assays revealed that photoaged sebaceous gland cells exhibited resistance to apoptosis. Transmission electron microscopy further identified features indicative of ferroptosis. UVB exposure led to increased intracellular reactive oxygen species, decreased expression of the ferroptosis-related protein glutathione peroxidase (GPX)-4, and elevated levels of long-chain fatty acid-CoA ligase (ACSL)-4 and nuclear receptor coactivator (NCOA)-4. Further experiments confirmed that GDF11 overexpression increased the percentage of apoptotic cells and down-regulated GPX4 and ACSL4 expression, whereas GDF11 knockdown produced the opposite effects. These results suggest that GDF11 mitigates sebocyte photoaging via the ferroptosis pathway and highlight its potential as a therapeutic target.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell and Spatial Transcriptomics-Based Research Reveals Association Between M2a Macrophages and Tumor Spread through Air Spaces in Lung Adenocarcinoma.","authors":"Yun Ding, Han Zhang, Hui Wen, Shutong Zhao, Jiuzhen Li, Xin Liu, Kai Wang, Yangyun Huang, Meilin Xu, Daqiang Sun","doi":"10.1016/j.ajpath.2025.07.017","DOIUrl":"10.1016/j.ajpath.2025.07.017","url":null,"abstract":"<p><p>Tumor spread through air spaces (STAS) is a pathologic feature of lung cancer with prognostic significance, and it is also a cutting-edge hotspot in the clinical field of lung cancer. However, the current mechanisms underlying the occurrence and colonization of STAS in lung adenocarcinoma (LADC) remain unclear. Single-cell RNA sequencing combined with Digital Spatial Profiling spatial transcriptomics sequencing, which aligns well with the spatial characteristics of STAS and the tumor microenvironment, was innovatively used in this research to explore the mechanisms by which specific types of tumor-associated macrophages influence the occurrence and development of STAS in LADC. This study suggests that M2a macrophages are associated with STAS in LADC and patient prognosis. M2a macrophages may enhance STAS in LADC by promoting β-catenin signaling through the chemokine (C-C motif) ligand 17/CCR4 axis. Therefore, targeting tumor-associated macrophages could be a beneficial precision treatment strategy for patients with STAS-positive LADC. In addition, the tumor microenvironment exhibits significant spatial heterogeneity, and its spatial characteristics should be fully considered when studying tumors.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dehydroepiandrosterone Prevents Collagen Loss by Regulating HIF-1α Expression and Mitophagy in Hypoxic Human Scleral Fibroblasts.","authors":"Qi Zhang, Jing Chen, Haichun Li, Jing Yang, Jieyong Huang, Bingqian Liu, Shida Chen, Ping Lian, Lin Lu, Xiujuan Zhao","doi":"10.1016/j.ajpath.2025.07.018","DOIUrl":"10.1016/j.ajpath.2025.07.018","url":null,"abstract":"<p><p>Myopia progression and its associated complications, which can lead to vision impairment, primarily result from persistent abnormal elongation of the eye's axial length. The previous metabonomic analysis of intraocular fluids suggested intraocular hormones may play a role in high myopia pathogenesis. In this study, significantly reduced concentrations of dehydroepiandrosterone (DHEA) were discovered in the vitreous humor of high myopia eyes. Additionally, DHEA levels in retina tissues of myopic guinea pigs were significantly decreased, further linking intraocular DHEA depletion to myopia-related tissue changes. Recent research has established scleral hypoxia as a fundamental mechanism underlying myopia development, with scleral fibroblasts serving as key functional cells in this process. Thus, this study investigated the effects of DHEA on human scleral fibroblasts under hypoxic conditions to generate novel insights for myopia prevention and treatment. The findings demonstrated that DHEA down-regulates hypoxia-inducible factor 1α (HIF-1α) expression and reduces collagen loss under hypoxic conditions. Additionally, DHEA reversed the decreased cell proliferation observed in human scleral fibroblasts in vitro. These effects appear to be mediated through changes in mitochondrial dynamics and regulation of BNIP3L-mediated mitophagy induced by DHEA under hypoxia. The results suggest DHEA represents a promising novel therapeutic strategy for preventing myopia development.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Theory to Practice: A Comprehensive Review of Pseudomyxoma Peritonei Research and Its Implications for Future Treatment.","authors":"Han Gao, Hongli Wang, Xiufeng Li, Fulei Zhang, Yiru Ba, Jiatong Zhao, Chengwei He, Shuzi Xin, Xiaohui Liu, Guowei Liang","doi":"10.1016/j.ajpath.2025.08.005","DOIUrl":"10.1016/j.ajpath.2025.08.005","url":null,"abstract":"<p><p>Pseudomyxoma peritonei (PMP) is a rare disease characterized by symptoms such as mucinous ascites and omental cake, typically arising from a perforated epithelial tumor of the appendix. Because of its rarity, non-specific histologic characteristics, and slow progression, its pathogenesis and optimal treatment remain subjects of debate. PMP is still a challenging and enigmatic condition. Increasing global attention is being directed toward understanding its pathogenesis and establishing standard treatment approaches. PMP and mucin are inextricably linked. This article highlighted the important role of mucin in the disease's pathogenesis. It also discussed several potential therapeutic strategies for eliminating mucin in PMP. Tumor development and metastasis involve a series of steps that include the interaction between the tumor and the host-derived stromal environment, which promotes angiogenesis and activation of inflammatory cells. Inflammatory cytokines and chemokines play a crucial role in the progression and development of PMP. The microbiome and specific microorganisms may directly influence tumor development, progression, and responses to certain therapies in PMP. Thus, the article summarized the interactions among bacteria, the immune system, and mucin in PMP, focusing on the mechanisms that related to abnormal mucin and tumor growth. This review critically examined the existing literature on the clinical features, pathologic processes, and treatment options in PMP, aiming to guide future research toward identifying novel therapeutic targets and gut-related disease biomarkers.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Laminin Receptors in Peripheral Tissues: Functions Revealed by Analysis of Knockout Mice.","authors":"Wanling Xuan, Yao Yao","doi":"10.1016/j.ajpath.2025.08.007","DOIUrl":"10.1016/j.ajpath.2025.08.007","url":null,"abstract":"<p><p>Laminin, by interacting with its receptors (mainly integrins and dystroglycan), exerts a variety of important functions in multiple organs. Loss-of-function studies have described the essential roles of laminin receptors in both physiological and pathologic conditions. This review summarizes the pathology and loss-of-function phenotypes of laminin receptors, including integrin-α3, integrin-α6, integrin-α7, integrin-β1, integrin-β4, and dystroglycan, focusing on the skin, kidney, skeletal muscle, peripheral nervous system, mammary gland, lung, and heart. To explore the functional redundancy/compensation among different laminin receptors, the phenotypes of compound knockout mice are compared with that of single mutants. Next, key signaling pathways downstream of each laminin receptor are summarized and compared. In addition, key questions in the field and future directions are also discussed. The aim of this review was to provide a synthetic review on loss-of-function studies of laminin receptors and foster the formation and testing of new hypotheses in the field.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Extracellular Vesicle-Derived miRNA in the Atherosclerotic Burden.","authors":"Alessandra Stefania Rizzuto, Isabella Fichtner, Stefano Carugo, Annalisa Radeghieri, Chiara Macchi, Massimiliano Ruscica","doi":"10.1016/j.ajpath.2025.08.006","DOIUrl":"10.1016/j.ajpath.2025.08.006","url":null,"abstract":"<p><p>In the context of atheroma-related sequelae, the role of extracellular vesicles (EVs) continues to spike interest. Their ability to traffic molecular cargo between cells highlights their role in intercellular communication, and consequently their involvement in mediating molecular events at the basis of physiological and pathologic processes. EVs encapsulate miRNAs within their lumen, shielding them from circulating ribonucleases, which would otherwise catalyze their degradation. However, there is an ongoing debate regarding the implication of miRNA contained within EVs in modulating biological activities on a molecular level. Therefore, the aim of the present review is to discuss the role of EV-derived miRNA, focusing on their implication in molecular mechanisms underlying atheroma formation. EVs of endothelial origin can regulate monocyte activation by transferring miR-10a that targets components of the inflammatory pathway. Tail vein administration of EVs derived from endothelial cells enriched in miR-34c-5p markedly reduces atherosclerosis progression. In patients with stable coronary artery disease, elevated levels of miR-126 and miR-199a in circulating EVs are significantly associated with a reduced incidence of major adverse cardiovascular event rate. These nanoparticles, released by all cells into most biological fluids, hold promise as a liquid biopsy tool as their circulating patterns and cargo can reflect the onset and severity of cardiovascular diseases.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}