The Journal of Pathology最新文献

{"title":"In-frame variants in TP53 gene identified in adult leukemia samples are predominantly deleterious: a study of the TP53 Network of Education and Research Initiative on CLL.","authors":"Šárka Pavlová, Johana Gombíková, Silvia Petrezsélyová, Libor Macůrek, Marcela Ženatová, Marie Zádrapová, Anna Panovská, Eva Zapletalová, Blanca Ferrer Lores, Alicia Serrano Alcalá, Eugen Tausch, Stephan Stilgenbauer, Fanny Baran-Marszak, Gregory Lazarian, Miguel Alcoceba, Ana Balanzategui, Lisa Bonello, Ivana Ježíšková, Martina Sopkovičová, Silvia Zibellini, Marzia Varettoni, Audrey Bidet, Helena Podgornik, Sandra Šućurović, Riccardo Moia, Mónica López-Guerra, Mark Catherwood, Šárka Pospíšilová, Jitka Malčíková","doi":"10.1002/path.70124","DOIUrl":"https://doi.org/10.1002/path.70124","url":null,"abstract":"<p><p>The prognostic and predictive impact of TP53 variants in leukemia led to their inclusion in diagnostic and treatment guidelines, increasing the demand for rapid, reliable laboratory analysis, interpretation, and reporting. While most TP53 variants identified in tumor samples can be interpreted using data from large-scale functional studies, evidence regarding the impact of in-frame deletions and insertions not disturbing the reading frame remains limited. Consequently, the classification of somatic in-frame variants often relies on expert judgment rather than standardized criteria. To address this gap, we collected in-frame TP53 variants identified during routine diagnostic testing in laboratories within the TP53 Network of Education and Research Initiative on Chronic Lymphocytic Leukemia (ERIC). We analyzed 60 leukemia samples from 13 laboratories, comprising 54 distinct variants. Initial classification using existing data and interpretation guidelines assigned these variants predominantly to the category of variants of uncertain significance. Functional analyses using a yeast-based transactivation assay, complemented by testing selected variants in the TP53-knockout RPE1 cell line, showed a nonfunctional phenotype for the vast majority of in-frame TP53 variants. This indicates that most in-frame alterations detected in leukemia samples are functionally deleterious, as further supported by their association with second-allele inactivation and frequent clonal expansion in relapse. With respect to variant localization, we observed that 49 variants located within the core region of the DNA-binding domain showed complete loss of transactivation function. The five variants located downstream of codon 286 exhibited heterogeneous functional phenotypes depending on their localization and the experimental system used. In conclusion, the integration of our findings with published functional data supports the interpretation that in-frame TP53 variants within the core DNA-binding domain identified in tumor samples are likely pathogenic. Conversely, interpretation of less frequent in-frame variants outside this region requires integration of multiple evidence, including functional studies, published literature, and curated variant databases. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035912","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":"Targeting PPP1R14B overcomes immunotherapy resistance in prostate cancer by restoring CD8⁺ T-cell infiltration via the Nrf2/CX3CL1 axis.","authors":"Jie Yang, Chuan Zhou, Wenbo Zhang, Han He, Jia Wang, Chao Wang, Fenghai Zhou","doi":"10.1002/path.70133","DOIUrl":"10.1002/path.70133","url":null,"abstract":"<p><p>Prostate cancer (PCa) is typically immunologically 'cold', which limits the effectiveness of immunotherapy, and this study sought to identify key genes driving this immunosuppressive phenotype and assess their therapeutic potential. We analyzed transcriptomic data from 487 TCGA-PRAD patients and three Gene Expression Omnibus datasets; weighted gene co-expression network analysis was used to identify cancer-related genes, TIMER to evaluate their influence on the tumor microenvironment, and findings were validated via flow cytometry on 32 clinical PCa specimens. Immunoblotting measured Nrf2, p-AKT, and p-GSK-3β levels, while ChIP-qPCR assessed Nrf2 and RNA polymerase II binding to the CX3CL1 promoter, and functional studies were conducted in allograft and xenograft mouse models using GapmeR antisense oligonucleotides combined with anti-PD-1 antibodies or PSMA-targeted CAR-T cells. We found PPP1R14B (PP1 regulatory inhibitor subunit 14B) was overexpressed in PCa and associated with poor prognosis, promoting PCa cell proliferation, suppressing apoptosis, and correlating with increased tumor purity but reduced CD8⁺ T-cell infiltration; mechanistically, CX3CL1 was regulated by Nrf2 and PPP1R14B elevated p-AKT/p-GSK-3β to stabilize Nrf2, which bound the CX3CL1 promoter, suppressed its expression, and impaired CD8⁺ T-cell chemotaxis. GapmeR-mediated PPP1R14B knockdown suppressed tumor growth and enhanced anti-PD-1/CAR-T efficacy in mice, indicating PPP1R14B is a promising target to overcome PCa immunotherapy resistance. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023414","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":"Lactate and lactylation in cancer: metabolic regulation, immune modulation, and therapeutic opportunities.","authors":"Jiayi Chen, Anqi He, Siyi Zhu, Yong Xia, Lin Yang","doi":"10.1002/path.70132","DOIUrl":"https://doi.org/10.1002/path.70132","url":null,"abstract":"<p><p>Lactate has emerged from being viewed as a glycolytic byproduct to a central metabolic and signaling hub that coordinates tumor evolution and therapeutic adaptation. This review integrates current evidence on how lactate production, transport, and accumulation reshape cancer biology, with particular emphasis on the lactate-lactylation axis. In tumors, lactate is generated not only by malignant cells through aerobic glycolysis, hypoxia-driven metabolic rewiring, and glutamine-derived carbon flow, but also by stromal cells, immune cells, adipocytes, and tumor-associated microbiota. Through monocarboxylate transporter-mediated shuttling, lactate supports metabolic symbiosis, extracellular acidification, matrix remodeling, angiogenesis, invasion, and immune escape. Beyond these metabolic and signaling functions, lactate acts as a substrate for lysine lactylation, linking altered metabolism to epigenetic and post-translational regulation. Histone and nonhistone lactylation, governed by emerging writers, erasers, and putative readers, regulates transcription, DNA damage repair, cancer stemness, ferroptosis resistance, immune checkpoint expression, and resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We further discuss the biomarker potential of lactate-related enzymes, transporters, site-specific lactylation marks, and therapeutic strategies targeting lactate production, transport, sensing, depletion, and lactylation machinery. A deeper understanding of lactate flux and lactylation-dependent vulnerabilities may enable biomarker-guided combinations that integrate metabolic intervention, epigenetic modulation, and immuno-oncology for precision cancer therapy. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023338","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":"A scalable workflow for sensitive detection and genomic profiling of tumour cells in lymph nodes from FFPE tissue.","authors":"Tristan Bergmann, Marianne Hölbling, Monica Sudarsanam, Christiane Driemel, Maximilian E Daniels, Joanna Swierz, Sandra Jaschinski, Maximilian Seidl, Norbert R Kübler, Wolfram T Knoefel, Rui Pl Neves, Karl C Sproll, Nikolas H Stoecklein","doi":"10.1002/path.70122","DOIUrl":"https://doi.org/10.1002/path.70122","url":null,"abstract":"<p><p>Accurate detection of lymph node (LN) metastases is critical for prognosis and surgical decision-making in head and neck squamous cell carcinoma (HNSCC) and other epithelial cancers. Standard histopathology examines only a small fraction of LN tissue, limiting sensitivity for micrometastases and isolated tumour cells. Scalable approaches are needed to improve staging accuracy and reduce overtreatment. We adapted the FDA-approved CELLSEARCH System, originally developed for circulating tumour cell detection, for use on dissociated 50 μm formalin-fixed paraffin-embedded (FFPE) LN sections. Tumour cells were enriched via EpCAM-based immunomagnetic capture, stained with cytokeratin (CK)/DAPI and quantified using the ACCEPT (Automated CTC Classification, Enumeration and Phenotyping Technology) image analysis tool. Specificity and reproducibility were tested in 50 metastasis-positive and 50 metastasis-free LNs from patients with HNSCC. Enriched cells underwent single-cell and pooled whole-genome amplification (WGA), quality-controlled by a genomic integrity index and profiled for copy number alterations (CNA) by low-pass whole-genome sequencing. Tumour cells were detected in 100% of LN metastases (range: 37-12,479), with counts strongly correlating with histological tumour area (p < 0.0001). Rare background events in control LNs were excluded by manual CELLSEARCH review. Based on their frequency, a threshold of > 12 cells was defined to classify samples as positive, yielding an assay specificity and sensitivity of 100%. Reproducibility across adjacent sections was high. Despite FFPE preservation, WGA succeeded in 27% of single cells and > 75% of pooled fractions. CNA profiling yielded 50 high-quality tumour genomes, revealing typical HNSCC alterations and marked inter-/intra-patient heterogeneity. This adapted CELLSEARCH workflow enables sensitive detection and genomic profiling of tumour cells from FFPE LN tissue. Demonstrated in HNSCC as a proof of concept, the approach is broadly applicable to epithelial cancers where LN staging is prognostically decisive. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015086","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":"Optical genome mapping enhanced by refined variant interpretation in pediatric acute lymphoblastic leukemia","authors":"Anna Bekő,&nbsp;Borbála Péterffy,&nbsp;Alex Hughes,&nbsp;Janka Sára Jakab,&nbsp;Irén Haltrich,&nbsp;Kristóf Balázs Árvai,&nbsp;Gábor Bedics,&nbsp;Katalin Csonka,&nbsp;Gergő Papp,&nbsp;Dóra Kapczár,&nbsp;Bettina Aranka Bohusné Barta,&nbsp;Lajos László Hegyi,&nbsp;Gábor Szalóki,&nbsp;Gábor Barna,&nbsp;András Matolcsy,&nbsp;Bálint Egyed,&nbsp;Zsuzsanna Hevessy,&nbsp;Anne Benard-Slagter,&nbsp;Sander Palit,&nbsp;Suvi Savola,&nbsp;Csaba Bödör,&nbsp;Donát Alpár","doi":"10.1002/path.70096","DOIUrl":"10.1002/path.70096","url":null,"abstract":"<p>Reliable detection of structural variants (SVs) and copy number variations (CNVs) is crucial in the contemporary diagnostics of pediatric B-cell acute lymphoblastic leukemia (B-ALL). However, limitations of commonly used conventional and molecular cytogenetic methods may hinder the accurate genetic characterization of patients. Optical genome mapping (OGM) offers a reliable alternative by enabling high-resolution, genome-wide detection of CNVs and SVs. Chromosomal aberrations were screened using OGM in 51 children with B-ALL. The results were compared with those of karyotyping, fluorescence <i>in situ</i> hybridization (FISH), digital multiplex ligation-dependent probe amplification (digitalMLPA), and targeted RNA sequencing (RNA-seq). OGM data showed high congruency with karyotyping and FISH findings, detecting clinically relevant variants beyond G-banding results and unraveling a complex <i>KMT2A</i> fusion undetected by FISH. Gene fusions involved in complex <i>ETV6</i>::<i>RUNX1</i> translocations, but not detected by RNA-seq, were confirmed using FISH. Normalization of OGM copy number values with DNA-index-improved concordance with FISH-derived copy numbers in near-tri/tetraploid cases. In the peripheral regions of OGM variants (fringe-zones), a novel evaluation strategy called ‘<i>FriZone</i>’ was applied, which significantly improved the concordance between OGM and digitalMLPA. In addition, a co-segregation analysis revealed strong associations between <i>ETV6</i>::<i>RUNX1</i> fusion and deletions of <i>ETV6</i>, <i>RAG2</i>, and <i>NR3C2</i>. OGM uncovered complex rearrangements undetected by widely used methods in 15% of cases, improving genetic classification and risk stratification in 10% of the patients. The <i>FriZone</i> analysis and normalization by DNA-index provide a refined, more accurate approach to OGM variant interpretation, facilitating the efficient application of OGM in clinical diagnostics. © 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":"270 2","pages":"241-254"},"PeriodicalIF":5.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70096","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676232","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":"Diversified cell origin of Helicobacter pylori eradication-responsive gastric diffuse large B-cell lymphomas","authors":"Sung-Hsin Kuo,&nbsp;Kun-Huei Yeh,&nbsp;Chung-Wu Lin,&nbsp;Li-Tzong Chen,&nbsp;Jyh-Ming Liou,&nbsp;Chia-Tung Shun,&nbsp;Hsiao-Wei Lee,&nbsp;Ming-Feng Wei,&nbsp;Hsiu-Po Wang,&nbsp;Ming-Shiang Wu,&nbsp;Ann-Lii Cheng","doi":"10.1002/path.70091","DOIUrl":"10.1002/path.70091","url":null,"abstract":"<p>A significant proportion of gastric diffuse large B-cell lymphoma with mucosa-associated lymphoid tissue [DLBCL(MALT)] and without MALT (‘pure’ DLBCL) can be resolved by <i>Helicobacter pylori</i> eradication (HPE). Gastric MALT lymphoma is an indolent lymphoma derived from memory B cells in the marginal zone. In the present study, we aimed to explore the origin of large cells in HPE-responsive gastric DLBCLs (complete remission after HPE). We investigated gastric lymphoma biopsies from 31 patients with HPE-responsive DLBCLs [15 ‘pure’ DLBCLs, 16 DLBCL(MALT)s]. We used the Hans algorithm (CD10, BCL-6, and MUM1) to define the origins of germinal center B cell (GCB) and non-GCB. To further ascertain the cellular origin, 11 ‘pure’ DLBCLs were examined using an Agilent whole-human genome microarray. Eleven DLBCLs [eight with ‘pure’ DLBCL and three with DLBCL(MALT)] were also assessed using Lymph2Cx. Specific GCB markers, including BACH2, AID, and <i>BCL2</i> rearrangement and enhancer of zeste 2 polycomb repressive complex 2 subunit (<i>EZH2</i>) codon 641 mutations, were evaluated in 31 patients with HPE-responsive gastric DLBCLs. According to the Hans algorithm, 53% (8/15) of gastric ‘pure’ DLBCLs and 50% (8/16) of DLBCL(MALT)s were of the GCB phenotype. Gene expression assays revealed that five of six patients with ‘Hans’ GCB had GCB genetic signatures, whereas four of five patients with ‘Hans’ non-GCB had activated B-cell genetic signatures. The Lymph2Cx assay revealed the GCB subtype in seven of eight patients with ‘Hans’ GCB. The expression patterns of BACH2 (<i>p =</i> 0.005) and AID (<i>p =</i> 0.038) closely correlated with the ‘Hans’ GCB phenotype. <i>BCL2</i> rearrangements and <i>EZH2</i> codon 641 mutations were detected in 44% (7/16) and 13% (2/16) of patients with ‘Hans’ GCB, respectively. In another cohort of 29 HPE-unresponsive gastric DLBCLs [19 ‘pure’ DLBCLs and 10 DLBCL(MALT)s], we found a close association between the ‘Hans’ GCB subtype and the GCB subtype as determined by the Agilent whole-human genome microarray and Lymph2Cx in lymphoma cells of these patients. In conclusion, more than half of HPE-responsive large cell lymphoma cases in the stomach were of GCB origin. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 2","pages":"174-193"},"PeriodicalIF":5.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148672681","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":"Bronchiolar adenoma-like lesions with atypical features beyond the classic morphological spectrum: integrating histomorphology and molecular profiles","authors":"Jiayu Li,&nbsp;Yunzhu Li,&nbsp;Yanqin Tan,&nbsp;Chengmin Zhou,&nbsp;Xiaohong Yao,&nbsp;Jieyu Wang,&nbsp;Yehan Zhou,&nbsp;Yang Liu,&nbsp;Ting Lan","doi":"10.1002/path.70092","DOIUrl":"10.1002/path.70092","url":null,"abstract":"<p>Bronchiolar adenoma (BA) is a rare benign pulmonary neoplasm defined by a bilayered architecture with a continuous basal cell layer. Increasingly, BA-like lesions with atypical features have been recognized, challenging established diagnostic boundaries and raising questions regarding their malignant potential. In this study, we investigated the clinicopathological and molecular characteristics of such lesions. We retrospectively analyzed 19 BA-like lesions that retained at least focal classic BA morphology and exhibited one or more predefined atypical features, including basal cell hyperplasia (with or without squamous dysplasia), partial-to-complete loss of the basal cell layer, stromal-like growth, cytological atypia exceeding classic BA, or morphologically contiguous carcinoma components. Patients showed a broad age distribution with a slight female predominance, and all cases with available follow-up remained disease-free following complete surgical resection (median 29.6 months; range 5–64 months). Histologically, atypical changes involved both basal and luminal compartments, resulting in mixed biphasic and monolayered areas, stromal-like growth, squamous metaplasia or dysplasia, and variable degrees of cytological atypia. Whole-exome sequencing (10 cases) and targeted profiling (two cases) revealed heterogeneous genetic alterations, including driver events involving <i>BRAF</i>, <i>EGFR</i>, and <i>MET</i>, as well as recurrent mutations affecting <i>HRAS</i>, <i>PIK3CA</i>, <i>MTOR</i>, DNA repair genes, and epigenetic regulators. Pathogenic <i>TP53</i> mutations were confined to lesions with marked epithelial atypia. At the pathway level, MAPK alterations, including <i>HRAS</i> mutations, were enriched in basal-hyperplasia lesions, whereas PI3K/AKT/mTOR alterations were more frequent in basal-deficient lesions. These findings support the concept that BA-like lesions with atypical features represent a morphological continuum ranging from benign BA to malignant lesions. We further propose a pragmatic framework for diagnosis and clinical management, although validation in larger cohorts with longer follow-up is required. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 2","pages":"194-210"},"PeriodicalIF":5.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403120","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":"Immune dysregulation in the prostates of C57BL/6Aire−/− mice mirrors that seen in human benign prostatic hyperplasia","authors":"Nadia A Lanman,&nbsp;Meaghan M Broman,&nbsp;Harish Kothandaraman,&nbsp;Gregory M Cresswell,&nbsp;Gada D Awdalkreem,&nbsp;Dilinaer Wusiman,&nbsp;Andree K Kolliegbo,&nbsp;Alexander P Glaser,&nbsp;Brian T Helfand,&nbsp;Renee E Vickman,&nbsp;Jiang Yang,&nbsp;Simon W Hayward,&nbsp;Timothy L Ratliff","doi":"10.1002/path.70093","DOIUrl":"10.1002/path.70093","url":null,"abstract":"<p>Benign prostatic hyperplasia (BPH) is the most common urologic disease in aging men, resulting in significant morbidity. The etiologies of BPH are unknown, though chronic prostatic inflammation is known to promote hyperplasia, fibrotic remodeling, and therapeutic resistance in BPH. BPH is highly complex and heterogeneous, presenting with varying degrees of stromal and epithelial proliferation, fibrosis, inflammation, and associated lower urinary tract symptoms. This complexity poses challenges in developing models. Here, we characterize an <i>Aire</i> transcription factor-deficient nonresolving (chronic) inflammation model in a C57BL/6J background for the study of the prostatic inflammation present in BPH. This chronic inflammatory model exhibits a lack of central tolerance but retains an otherwise intact and functional immune system. C57BL/6^{<i>Aire</i>−/−} mice were subcutaneously injected with prostate homogenate protein and Freund's Complete Adjuvant and boosted after 10 days. After 21 and 35 days, whole prostates were collected for histology, flow cytometry, and single-cell RNA sequencing (scRNA-seq), which were then compared to human BPH data. Inflammation was confined to the prostate in C57BL/6^{<i>Aire</i>−/−} mice. Histological and scRNA-seq data show that the dominant leukocyte phenotypes in the prostates of C57BL/6^{<i>Aire</i>−/−} mice are B and T lymphocytes. Macrophages in C57BL/6^{<i>Aire</i>−/−} mouse prostates express signatures associated with an array of phenotypes, as also seen in BPH. We identify a <i>Trem2</i>⁺ population of macrophages and aging-associated Cd8⁺ <i>GZMK</i> hi <i>GZMB</i> low T cells in C57BL/6^{<i>Aire</i>−/−} prostates similar to those seen in human BPH. Further, fibroblast clusters in C57BL/6^{<i>Aire</i>−/−} are similar to fibroblasts identified from the prostates of patients diagnosed with BPH, and these clusters also express markers associated with aging. Overall, the inflammation and predicted leukocyte--stromal interactions observed in the prostates of C57BL/6^{<i>Aire</i>−/−} mice resemble human BPH, likely at the early stages of the disease, making this model useful for studying the impact of inflammation-driven prostatic hyperplasia. © 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":"270 2","pages":"211-225"},"PeriodicalIF":5.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70093","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409810","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":"Differences between mitotically old and young endometrial tumors","authors":"Kellie Kim,&nbsp;Darryl Shibata","doi":"10.1002/path.70090","DOIUrl":"10.1002/path.70090","url":null,"abstract":"<p>Human tumors likely differ in their mitotic ages, reflecting how many divisions elapse between the final tumor progenitor cell and surgical removal. We used a rapidly fluctuating CpG (fCpG) methylation clock to infer relative endometrial adenocarcinomas (EAC) mitotic ages. Experimentally, young tumors initiated from single cells show low-diversity, high-variance fCpG distributions with trimodal peaks near 0%, 50%, and 100%, reflecting inherited progenitor methylation states. fCpG methylation becomes polymorphic with divisions, and older tumors exhibit higher diversity, lower variance, and unimodal distributions centered around 50%. Mitotic ages varied across EAC samples. Synchronous hyperplasia and invasive regions generally shared similar ages, and primary–metastatic EAC pairs showed both synchronous and stepwise progression. The Cancer Genome Atlas (TCGA) EACs also showed variable mitotic ages: younger tumors were enriched for proliferation pathways, whereas older tumors showed more immune infiltration, immune-pathway activation, and evidence of T-cell exhaustion. These results show that human tumors can be ranked by mitotic age and suggest that the growth of older cancers is restrained by immune surveillance. © 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":"270 2","pages":"163-173"},"PeriodicalIF":5.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403033","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":"Applying flow cytometry-based isolation of platelet-derived microparticles to banked human plasma for cellular studies","authors":"Nima Fattahi,&nbsp;Tarun Tyagi,&nbsp;Fallyn Kirlin,&nbsp;Andrea De La Lama Flores,&nbsp;John Hwa,&nbsp;Yasuko Iwakiri,&nbsp;Matthew J McConnell","doi":"10.1002/path.70097","DOIUrl":"10.1002/path.70097","url":null,"abstract":"<p>Platelet-derived microparticles (PMPs) constitute the majority of circulating microparticles in blood. PMPs carry cargo including RNA, protein, and miRNA, and play key pathophysiologic intercellular signaling roles in cardiovascular, autoimmune, and liver diseases. Most methods use fresh platelets treated with an agonist to generate PMPs, which has restricted the size and feasibility of human studies. With the rise of large biobanks, such as the UK Biobank (https://www.ukbiobank.ac.uk/), and because microparticles are retained in cryopreserved plasma, this study aimed to develop an efficient and reproducible method to isolate PMPs from banked cryopreserved human plasma to investigate their communication with target cells. We employed flow cytometry using 180–1,300 nm size calibration beads and the platelet-specific marker CD41 to identify and sort PMPs based on size and CD41 positivity. Following isolation, microparticle size and morphology were validated by electron microscopy and nanoparticle tracking analysis. To assess the utility of the microparticles for studies of cell–cell interactions, we visualized microparticle uptake into human umbilical vein endothelial cells and THP-1 cells. Our method enables the isolation and downstream analysis of human PMPs in cell–cell interactions, facilitating translational studies in large populations and rare diseases. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 2","pages":"131-138"},"PeriodicalIF":5.4,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434520","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}