The Journal of Pathology最新文献

{"title":"Dopamine inhibits retinal pathological neovascularization in the oxygen-induced retinopathy mouse model","authors":"Qi Wang,&nbsp;Jiajia Shi,&nbsp;Shuai Ouyang,&nbsp;Tingting Zhang,&nbsp;Haoran Yang,&nbsp;Jiadi Zhu,&nbsp;Luyao Wang,&nbsp;Yuan Lv,&nbsp;Sisi Dong,&nbsp;Ruyi Chen,&nbsp;Xuemei Ling,&nbsp;Shiming Jiao,&nbsp;Mengmeng Dong,&nbsp;Wenjun Yan,&nbsp;Jinglei Yang,&nbsp;Biao Yan,&nbsp;Jiangfan Chen,&nbsp;Jia Qu,&nbsp;Fei Zhao,&nbsp;Xiangtian Zhou","doi":"10.1002/path.70080","DOIUrl":"10.1002/path.70080","url":null,"abstract":"<p>Pathological neovascularization is the leading cause of childhood blindness in retinopathy of prematurity (ROP). Anti-vascular endothelial growth factor agents are commonly used to treat this condition, yet their variable efficacy and off-target effects demand alternative strategies. Here, we investigated the relationship between retinal dopamine (DA) dynamics and pathological angiogenesis in the oxygen-induced retinopathy (OIR) mouse model mimicking ROP pathogenesis. We determined the individual effects of apomorphine (APO), a non-selective DA receptor agonist, and selective agonists or antagonists of dopamine D1 receptor (Drd1) and dopamine D2 receptor (Drd2), on pathological neovascularization. Integrating single-cell RNA sequencing with Müller cell-specific <i>Drd2</i> knockout OIR mice, we identified that Drd2-mediated signaling in Müller cells orchestrates hypoxia-inducible factor alpha and vascular endothelial growth factor A biosynthesis in Müller cells during the hypoxic–ischemic phase of OIR. Collectively, OIR-induced dopaminergic deficiency and impaired Drd2 activity in Müller cells synergistically exacerbate pathological angiogenesis. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 1","pages":"40-54"},"PeriodicalIF":5.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154514","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":"FTO-mediated m6A modification of protein disulfide-isomerase activates VEGFA–VEGFR2 to suppress programmed cell death in osteosarcoma","authors":"Jiashi Wang,&nbsp;Yingying Hao,&nbsp;Ming He,&nbsp;Weizheng Zhou","doi":"10.1002/path.70083","DOIUrl":"10.1002/path.70083","url":null,"abstract":"<p>Osteosarcoma (OS) is a primary bone malignancy, and its progression can be hindered by inducing programmed cell death (PCD). Protein disulfide-isomerase (PDI) regulates cancer cell death; however, its functional role in OS remains unclear. <i>P4HB</i> expression was assessed in tumor tissues and cells from patients with OS using RT-qPCR. The effects of <i>P4HB</i> on OS cell lines were evaluated. Western blotting was used to assess the impact of P4HB on various forms of PCD (apoptosis, ferroptosis, and pyroptosis). Bioinformatics analysis identified the upstream and downstream mechanisms of <i>P4HB</i> in OS progression. A xenograft tumorigenesis study was performed to elucidate the role and mechanism of <i>P4HB</i> in OS progression. Elevated <i>P4HB</i> expression was observed in OS tissue samples and cell lines. Downregulation of <i>P4HB</i> suppressed OS cell growth, migration, and invasiveness and induced PCD. Functional enrichment analysis and experimental validation revealed that PDI upregulated vascular endothelial growth factor A (VEGFA) vascular endothelial growth factor receptor 2 (VEGFR2) signaling. Methylation analysis showed that the m6A demethylase fat mass and obesity-associated protein (FTO) decreased <i>P4HB</i> m6A levels and enhanced VEGFA–VEGFR2 signaling in OS cells. Moreover, <i>FTO</i> overexpression enhanced the proliferative, migratory, and invasive capabilities of OS cells and decreased PCD. Finally, <i>FTO</i> knockdown inhibited tumor growth and lung metastasis of OS by decreasing the activity of the PDI/VEGFA–VEGFR2 signaling axis. Mechanistically, <i>FTO</i>-mediated m6A modification of <i>P4HB</i> regulates PCD in OS through activation of this axis. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 1","pages":"69-82"},"PeriodicalIF":5.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148160926","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":"Immunological mechanisms underlying the clinical heterogeneity of Kikuchi disease: the potential role of atypical memory B cells","authors":"Shan-Chi Yu,&nbsp;Kung-Chao Chang,&nbsp;Tseng-Cheng Chen,&nbsp;Chun-Nan Chen,&nbsp;Tsung-Lin Yang","doi":"10.1002/path.70068","DOIUrl":"10.1002/path.70068","url":null,"abstract":"<p>Building on our previous research, which classified Kikuchi disease into three subtypes based on predominant symptoms and fever status – febrile type, febrile lymphadenopathy (FebLAP), and afebrile lymphadenopathy (aLAP) – we further investigated the underlying mechanisms contributing to their distinct clinical differences. Using NanoString nCounter technology, we analyzed the gene expression profiles of 35 Kikuchi disease lymph node specimens and compared them across the subtypes. Compared with the febrile type, aLAP exhibited higher <i>AICDA</i> expression, a trend observed in both germinal center positive and negative cases. The aLAP specimens also showed higher expression of B-cell markers; however, CD20 immunohistochemical staining did not reveal an increased number of B cells in aLAP. We therefore hypothesize that aLAP contains a higher proportion of atypical memory B cells, characterized by elevated <i>AICDA</i> and B-cell marker expression compared with other B-cell subsets. Immunohistochemical staining demonstrated that IRTA1+ atypical memory B cells were present in 64% (23/36) of aLAP cases, significantly higher than in FebLAP (0/8, 0%) and the febrile type (2/11, 18%) (<i>p</i> &lt; 0.001). This finding confirms that aLAP is more likely to contain atypical memory B cells compared with the other subtypes. Pathway analysis revealed that the febrile type upregulates pathways associated with TLR2 and TLR4 signaling and neutrophil degranulation, while aLAP upregulates the TNFR2 non-canonical NF-κB pathway. RNAscope <i>in situ</i> hybridization demonstrated higher <i>TLR4</i> expression in the febrile type compared with the aLAP type. These findings suggest that the triggering microbes for each subtype may differ, leading to distinct immune responses and clinical presentations. Overall, these results provide new insights into the immunopathogenesis of Kikuchi disease and highlight the potential role of atypical memory B cells in shaping its distinct clinical presentations. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 4-5","pages":"399-411"},"PeriodicalIF":5.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758471","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 heterogeneity of Fuchs endothelial corneal dystrophy†","authors":"Sangita P Patel","doi":"10.1002/path.70062","DOIUrl":"10.1002/path.70062","url":null,"abstract":"<p>Late-onset Fuchs endothelial corneal dystrophy (FECD) is characterized by distinct extracellular matrix deposits (guttae) within the basement membrane (Descemet's membrane) of the corneal endothelium. In a recent study published in <i>The Journal of Pathology</i>, Vaitinadapoulé <i>et al</i> (2026) describe the diversity of guttae patterns in FECD through analysis of 500 Descemet's membrane specimens removed during surgery, with genotyping performed in one-fifth of patients for the commonly associated <i>TCF4</i> trinucleotide repeat expansion. The diversity and clustering of guttae phenotypes in the total cohort and in those with and without <i>TCF4</i> association have implications for commonly used diagnostic grading criteria for FECD, the development of therapeutics, and our understanding of disease development. Investigating and embracing this diversity holds promise for advancing our understanding of FECD. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 4-5","pages":"383-386"},"PeriodicalIF":5.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147626489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Testican-1-MMP axis in tumour extracellular matrix (ECM) remodelling: interaction dynamics analysis and an in silico perspective","authors":"Sepideh Youssefi,&nbsp;Kiarash Saleki,&nbsp;Prerna Kadam,&nbsp;Amirreza Mazloomi,&nbsp;Abhik Mukherjee,&nbsp;Lodewijk V Dekker,&nbsp;Abdolrahman S Nateri","doi":"10.1002/path.70073","DOIUrl":"10.1002/path.70073","url":null,"abstract":"<p>The extracellular matrix (ECM) plays a pivotal role in facilitating tumour development, invasiveness, metastasis, and immunoevasive processes through dynamic ECM remodelling processes. Testican-1 (SPOCK1), an excretory matricellular proteoglycan, is suggested to exert a role in the facilitation of ECM remodelling processes through interacting with matrix metalloproteases (MMPs) and even its less known forms. The structural mechanisms of interactions between testican-1 and MMPs were studied, and their roles in tumour-promotion pathway processes were also examined using a computational approach and immunofluorescence validated by colocalisation technique analysis. A computational analysis using docking, molecular dynamics (MD), and systems biology analysis was employed. HDock and GROMACS were chosen to analyse binding affinity and testican-1 stability with 28 different MMPs. H-bond, free energy, and root mean square fluctuation (RMSF) analyses were performed to confirm the interactions in the testican-1–MMP complexes. The systems biology toolkit implemented in this study consisted of STRING, BioGRID, and Cytoscape, which were employed for testican-1 interaction network and pathway analysis. Kaplan–Meier survival analysis using the GEPIA2 tool was utilised to correlate <i>SPOCK1</i> gene expression and clinical survival measures for various malignancies. The docking analysis showed robust interactions between testican-1 and MMP23, MMP25, and MMP28. Additionally, testican-1–MMP complexes were confirmed to form stable interfaces based on comprehensive MD analysis, suggesting solid binding interfaces with the MMP-unique domain of testican-1. Our systems biology experiment indicated testican-1 as a central hub for interactions between immunoevasive and ECM remodelling processes. SPOCK expression was also shown to correlate with significant survival measures for different malignancies, revealing clinical implications in cancer. The testican-1–MMP computational analysis suggests testican-1 plays a pivotal role as a therapeutic target for a wide range of malignancies. SPOCK–MMP interactions could be targeted to interrupt tumour-promoting processes by arresting dynamic changes in the ECM, thereby improving patient survival. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 4-5","pages":"433-445"},"PeriodicalIF":5.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupted endocannabinoid signaling contributes to systemic inflammation in acute pancreatitis","authors":"Paula Goncalves-Romeu,&nbsp;Karina Cárdenas-Jaen,&nbsp;Enrique de-Madaria,&nbsp;José María Hernández,&nbsp;Lourdes Fluvià,&nbsp;Laura Torres-Ribas,&nbsp;Daniel Closa,&nbsp;Raquel Guillamat-Prats","doi":"10.1002/path.70076","DOIUrl":"10.1002/path.70076","url":null,"abstract":"<p>Acute pancreatitis (AP) is an inflammatory disease that can lead to systemic complications in severe cases. The endocannabinoid system has emerged as a potential modulator of inflammation in AP. We investigated the role of the endocannabinoid 2-arachidonoylglycerol (2-AG) and the cannabinoid receptors CB1 and CB2 during AP. A severity-dependent decrease in circulating 2-AG was found both in patients and a murine AP model. Restoring 2-AG – by avoiding its degradation via monoacylglycerol lipase inhibitor or direct 2-AG administration – reduced local and systemic inflammation, modulated peritoneal macrophage polarization, and mitigated lung injury. Notably, endocannabinoid system effects were consistent across sexes. Both cannabinoid receptors were involved in disease pathophysiology. Genetic <i>Cnr1</i> knockout and pharmacological CB2 blockade showed distinct and complementary roles of both receptors in regulating inflammation, immune infiltration, and pulmonary damage. These findings highlight a protective role for 2-AG and highlight the endocannabinoid system – and cannabinoid receptors in particular – as a promising therapeutic target to modulate inflammation and reduce systemic complications in acute pancreatitis. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 4-5","pages":"462-477"},"PeriodicalIF":5.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting fibrosis in the treatment of lower urinary tract dysfunction","authors":"Ajinkya R Limkar,&nbsp;Sophia M Vrba,&nbsp;Emily A Ricke,&nbsp;Zsuzsanna Fabry,&nbsp;Matthew S Lee,&nbsp;Kevin T McVary,&nbsp;William A Ricke","doi":"10.1002/path.70079","DOIUrl":"10.1002/path.70079","url":null,"abstract":"<p>Benign prostatic hyperplasia (BPH) is a widely prevalent age-associated disease that is the main contributor to lower urinary tract dysfunction (LUTD) in aging men. Although prostate fibrosis has been recognized as a contributor to BPH pathophysiology, there are not any clinically available therapeutics that target this aspect of disease progression. In this study, we evaluated the antifibrotic potential of thalidomide using both <i>in vitro</i> and <i>in vivo</i> models of BPH/LUTD. Using benign human prostate stromal cells stimulated with transforming growth factor β-1 (TGFβ1) followed by targeted transcriptomic profiling and assessment of canonical TGFβ signaling, we demonstrate that thalidomide attenuates expression of profibrotic genes, including extracellular matrix components. In aged male mice with LUTD, thalidomide administration led to a reduction in prostate collagen deposition and decreased organization of collagen fiber alignment. Functionally, thalidomide treatment improved LUTD in aged male mice, while prostate mass, androgen receptor expression and downstream signaling targets, and proliferative index remained unchanged, suggesting that the observed therapeutic effects are primarily mediated by antifibrotic mechanisms. Our findings highlight thalidomide's potential to modulate prostatic fibrosis and improve voiding function and support further investigation into the role of antifibrotic therapies as novel treatments for BPH/LUTD. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 4-5","pages":"493-503"},"PeriodicalIF":5.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic comparative study between canalicular adenoma and HMGA2::WIF1 canalicular-like pleomorphic adenoma","authors":"Ziyad Alsugair,&nbsp;Anne Champagnac,&nbsp;Maxime Fieux,&nbsp;Pierre Philouze,&nbsp;Philippe Ceruse,&nbsp;Brice Thamphya,&nbsp;Daniel Pissaloux,&nbsp;Franck Tirode,&nbsp;Nazim Benzerdjeb","doi":"10.1002/path.70070","DOIUrl":"10.1002/path.70070","url":null,"abstract":"<p>Canalicular adenoma (CA) is a benign salivary gland tumor predominantly affecting the upper lip and is characterized by monomorphic epithelial cells arranged in branching cords within a loose and vascularized stroma. Unlike pleomorphic adenoma (PA), CA lacks a chondroid matrix and exhibits specific histological features, such as high cuboidal to columnar cells arranged in one to two cell layers. A recently identified PA subtype, named ‘<i>HMGA2</i>-canalicular-like PA’, mimics the morphology of CA but affects major salivary glands, and harbors the <i>HMGA2</i>::<i>WIF1</i> fusion. Immunohistochemical markers including SOX10 positivity and p40/p63 negativity are shared between these entities, raising questions about their molecular differences. Therefore, the current study aimed to extensively compare the molecular profiles of CAs and <i>HMGA2</i>-canalicular-like PAs to better understand the mechanisms underlying their oncogenesis. In the present study, CAs and the <i>HMGA2</i>-canalicular-like PAs mostly shared similar histology and immunostaining, while the clinical presentations regarding tumor site and transcriptomic profiles were different. A novel finding was the overexpression of SOX2 in patients diagnosed with CA, in comparison to those diagnosed with <i>HMGA2</i>-canalicular-like PA. The CAs displayed significantly higher enrichment of hallmarks for Hedgehog signaling, IL2/STAT5 signaling, and apical surface, and significantly lower enrichment of hallmarks for apoptosis and mitotic spindle. Additionally, Gene Ontology enrichment analysis displayed significant enrichment of biological process for CAs in comparison to <i>HMGA2</i>-canalicular-like PAs for myofibril assembly, muscle filament sliding, actin–myosin filament sliding, and sarcomere organization. CAs and <i>HMGA2</i>-canalicular-like PAs exhibited similar histology and immunostaining but differed significantly in tumor site and transcriptomic profiles. The latter revealed significant activation of muscle-related transcriptional pathways, and overexpression of SOX2 in CAs. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 4-5","pages":"423-432"},"PeriodicalIF":5.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLEC14A correlates with neutrophil infiltration in hepatocellular carcinoma and mediates neutrophil recruitment across liver endothelial cells","authors":"Joanne M O'Rourke,&nbsp;Dean Kavanagh,&nbsp;Ayla O'Keeffe,&nbsp;Kylie Savoye,&nbsp;Kaiyi Yang,&nbsp;Daniel A Patten,&nbsp;Catherine E Willoughby,&nbsp;Josep M Llovet,&nbsp;Georgiana Neag,&nbsp;Helen L Reeves,&nbsp;Peter W Hewett,&nbsp;Neena Kalia,&nbsp;Tahir Shah,&nbsp;Yuk Ting Ma,&nbsp;Kelly Hunter,&nbsp;Joe Flint,&nbsp;Jack L McMurray,&nbsp;Owen Cain,&nbsp;Fabian Spill,&nbsp;Derek A Mann,&nbsp;Amy J Naylor,&nbsp;Victoria Heath,&nbsp;Christopher J Weston,&nbsp;Roy Bicknell,&nbsp;Shishir Shetty","doi":"10.1002/path.70077","DOIUrl":"10.1002/path.70077","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, and cases are predicted to rise dramatically over the next few years. Overcoming the immune microenvironment in HCC remains a challenge, and innate immune populations such as tumour-associated neutrophils can potentially impair the success of immunotherapy. Elucidating the mechanisms of neutrophil recruitment across liver endothelium could lead to new approaches to boost the efficacy of immunotherapy. CLEC14A is an endothelium-specific receptor regulating sprouting angiogenesis, upregulated in low shear environments. We found CLEC14A to be highly expressed in both HCC vessels and on vasculature during acute liver injury, leading us to hypothesise that CLEC14A may regulate neutrophil recruitment to the liver and HCC. We found that CLEC14A positively correlated with a neutrophil signature and infiltration in public datasets and surgically resected tissue from HCC. Spatial transcriptomics (ST) of CLEC14A^high- and CLEC14A^low-expressing tumours confirmed upregulation of myeloperoxidase in CLEC14A^high tumours and correlation with other shear-dependent markers but a negative correlation with vascular endothelial growth factor A. To build on our correlation studies, we explored the role of CLEC14A in neutrophil recruitment across liver endothelium. We undertook <i>in vitro</i> recruitment studies with flow-based human liver endothelial assays and <i>in vivo</i> models of neutrophil recruitment. Using siRNA knockdown of <i>CLEC14A</i> and specific blocking antibodies to CLEC14A, we found that <i>CLEC14A</i> knockdown blocked the firm adhesion of neutrophils to liver endothelium, but this was independent of its interaction with its known ligand MMRN2. Finally, we confirmed that <i>Clec14a</i> deficiency led to a significant reduction in neutrophil recruitment across the sinusoids in an ischaemia-reperfusion liver injury model. We unveil a link between the angiogenic receptor CLEC14A and neutrophil recruitment. Targeting of CLEC14A on tumour endothelium is potentially a new approach to regulating neutrophil infiltration in HCC. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 4-5","pages":"478-492"},"PeriodicalIF":5.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic analysis of primary lung interdigitating dendritic cell sarcomas","authors":"Mikhail S Ermakov,&nbsp;Juliana Faria Filipe,&nbsp;Sylvia Eidenhammer,&nbsp;German Ott,&nbsp;Iris Halbwedl,&nbsp;Karl Kashofer,&nbsp;Helmut Popper","doi":"10.1002/path.70066","DOIUrl":"10.1002/path.70066","url":null,"abstract":"<p>Interdigitating dendritic cell sarcomas (IDCSs) are rare tumors that commonly arise in the hematopoietic system and rarely outside. The genetic drivers of IDCS carcinogenesis are unknown; therefore, therapeutic options are limited. We investigated somatic gene mutations and copy-number alterations (CNAs) in nine IDCSs arising in the lung by whole-exome sequencing (WES) paired with shallow whole-genome sequencing (sWGS). Using a panel of immunohistochemical markers, follicular dendritic sarcomas and Langerhans cell sarcomas were excluded, and inflammatory myofibroblastic tumors were excluded based on morphology. The Ki-67 score was used to stratify the tumors into low-grade (≤ 20%) and high-grade (&gt; 20%) tumors. The main question addressed by the study was whether genetic aberrations can be identified in IDCSs and whether these are druggable. High-grade IDCSs showed a higher fraction of genome altered by CNA (48.42%) than low-grade IDCSs (18.15%) and tended to have greater tumor mutation burden (7.56 versus 0.88 mut/Mb; not significant). Heterogeneous gains on chromosome 17 were characteristic of almost all IDCS cases (eight of nine cases, 89%), independent of grade. CNA in cancer-actionable genes was independent of clinicopathological characteristics and included amplifications in <i>EGFR</i>, <i>MYC</i>, <i>MDM4</i>, <i>ERBB2</i>, <i>CCNE1</i>, and <i>BRAF</i> and losses in <i>MTAP</i>, <i>CDKN2A</i>, <i>CDKN2B</i>, <i>MLH1</i>, and <i>VHL</i>, as well as homozygous losses in <i>SMAD2/4</i>, <i>ATM</i>, and <i>TP53</i>. Somatic gene mutations in cancer-related genes were identified in seven of nine IDCSs. No common driver mutations were identified. The heterogeneous genetic landscape suggests a mixed etiology of IDCS carcinogenesis and genomic instability in high-grade tumors. Distinct druggable biomarkers have been identified in almost all tumors, providing novel therapeutic options. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 4-5","pages":"387-398"},"PeriodicalIF":5.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}