The Journal of Pathology最新文献

{"title":"An oncogenic role for EBV-encoded BILF1 in nasopharyngeal carcinoma","authors":"Anna KC Wong,&nbsp;Vinotheni Rajendran,&nbsp;Lucia Mundo,&nbsp;Wenbin Wei,&nbsp;Andrew I Bell,&nbsp;Max Robinson,&nbsp;Cristiana Bellan,&nbsp;Stefano Lazzi,&nbsp;Ciara Leahy,&nbsp;Pathmanathan Rajadurai,&nbsp;Yew Toong Liew,&nbsp;Narayanan Prepageran,&nbsp;Lawrence S Young,&nbsp;Kwok-Wai Lo,&nbsp;Paul G Murray,&nbsp;Ian C Paterson,&nbsp;Lee Fah Yap","doi":"10.1002/path.70069","DOIUrl":"10.1002/path.70069","url":null,"abstract":"<p>It is widely recognized that latent infection is the predominant mode of Epstein–Barr virus (EBV) infection in nasopharyngeal carcinoma (NPC) in which a specific set of latent genes is responsible for driving the development of the disease. However, the expression of these latent genes does not adequately explain the various transformed phenotypes of NPC cells. Using an established high-throughput quantitative reverse transcription PCR array, we found that several EBV lytic genes were more widely expressed in primary NPC tissues than previously recognized. We focused on a lytic gene, <i>BILF1</i>, which encodes a constitutively active G protein-coupled receptor (GPCR). We showed that <i>BILF1</i> was expressed in tumour cells from primary NPC tissues at both mRNA and protein levels, and in the absence of <i>BZLF1</i> expression. RNA sequencing analysis of <i>BILF1</i>-expressing immortalised nasopharyngeal epithelial (NPE) cells demonstrated that the profile of BILF1-regulated genes significantly overlapped with gene signatures of micro-dissected NPC, indicating that the expression of BILF1 is relevant to the pathogenesis of NPC. In accordance with these observations, pathway analysis of the transcriptome of <i>BILF1</i>-expressing cells showed the involvement of BILF1 in key biological processes typically deregulated in NPC. To examine whether BILF1 expression influenced epithelial cell behaviour, functional studies showed that BILF1 enhanced cell proliferation, migration, invasion and colony formation. In addition, BILF1 increased AKT activation in NPE cells, which was responsible for the increase in cell migration. Taken together, our data convincingly point to an oncogenic role for BILF1 in NPC. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 4-5","pages":"412-422"},"PeriodicalIF":5.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831746","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":"Identifying therapeutic targets in low-grade serous ovarian carcinomas with no specific molecular profile","authors":"Kathleen I Pishas,&nbsp;Karla J Cowley,&nbsp;Evanny Marinovic,&nbsp;Martin Köbel,&nbsp;Marta Llaurado-Fernandez,&nbsp;Hannah Kim,&nbsp;Shaine Chenxin Bao,&nbsp;Dalia Mizikovsky,&nbsp;Nathan J Palpant,&nbsp;Raunak Shrestha,&nbsp;Robert Vary,&nbsp;Jennii Luu,&nbsp;Liliane Meunier,&nbsp;Timothy Semple,&nbsp;Pilar Blancafort,&nbsp;Emily Golden,&nbsp;Paul A Cohen,&nbsp;Mark S Carey,&nbsp;Ian G Campbell,&nbsp;Kaylene J Simpson,&nbsp;Dane Cheasley","doi":"10.1002/path.70075","DOIUrl":"10.1002/path.70075","url":null,"abstract":"<p>Low-grade serous ovarian carcinoma (LGSOC) is a rare, indolent ovarian cancer subtype with limited effective therapies. Approximately 40% of cases lack canonical MAPK/ERK or PI3K/AKT/mTOR pathway alterations and are classified as having no specific molecular profile (NSMP). These patients have poor responses to chemotherapy, MEK inhibitors, and hormonal therapies, highlighting the need for alternative strategies. This study aimed to identify novel therapeutic targets in NSMP LGSOC. A high-throughput drug screen of 3,436 compounds (including FDA-approved, clinically tested, and investigational agents) was conducted across 12 LGSOC and one control ovarian epithelial cell line. EGFR inhibitors emerged as selective hits in NSMP cell lines and were further tested in two NSMP and two MAPK-mutant lines in combination with standard-of-care chemotherapy agents, carboplatin and paclitaxel. EGFR expression was assessed using RNA sequencing, DNA methylation profiling, and immunohistochemistry in primary tumors, followed by survival analysis based on expression levels. Unsupervised clustering of drug response data revealed subtype-specific vulnerabilities, with EGFR inhibitors showing marked cytotoxicity in all five NSMP lines (robust <i>Z</i>-score ≤ −2), and minimal activity in MAPK- and <i>USP9X</i>-mutant lines. EGFR inhibitors (avitinib, AV-412) showed selective, low-dose synergy with standard-of-care chemotherapy in NSMP models, with minimal and inconsistent effects in MAPK-mutant lines. NSMP tumors showed elevated <i>EGFR</i> mRNA and EGFR protein expression, associated with poor survival, advanced disease stage, and peritoneal involvement, and inversely correlated with MAPK mutations. These findings position EGFR overexpression as a defining and targetable feature of NSMP LGSOC and support further preclinical validation of EGFR inhibitors as a treatment strategy for this understudied cancer subtype. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 4-5","pages":"446-461"},"PeriodicalIF":5.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947144","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":"Unraveling the spatial landscape of dystrophinopathies: a transcriptomic approach to Becker and Duchenne muscular dystrophies","authors":"Laura GM Heezen,&nbsp;Qirong Mao,&nbsp;Stefan Nicolau,&nbsp;Claudio Novella Rausell,&nbsp;Julia van der Weerd,&nbsp;Jan Kueckelhaus,&nbsp;Rasya Gokul Nath,&nbsp;Jordi Diaz-Manera,&nbsp;Hermien E Kan,&nbsp;Erik H Niks,&nbsp;Maaike van Putten,&nbsp;Annemieke Aartsma-Rus,&nbsp;Kevin M Flanigan,&nbsp;Ahmed Mahfouz,&nbsp;Pietro Spitali","doi":"10.1002/path.70067","DOIUrl":"10.1002/path.70067","url":null,"abstract":"<p>Dystrophinopathies are caused by pathogenic variants in the <i>DMD</i> gene, resulting in partial (Becker) or complete loss (Duchenne) of dystrophin. Becker (BMD) and Duchenne muscular dystrophy (DMD) are characterized by progressive muscle wasting, fatty replacement, fibrosis, and loss of function. To study histopathological changes, we used Visium spatial transcriptomics to profile skeletal muscle biopsies of patients affected by dystrophinopathy (<i>n</i> = 8) and healthy controls (<i>n</i> = 4). We estimated the proportion of cell types and their spatial localization across samples applying a deconvolution strategy using previously published single-nucleus RNA-sequencing data. We identified genes enriched in fat patches and cell types such as fibroadipogenic progenitors (FAPs) in areas of active pathology. Using expression data of ligand–receptor pairs, we highlight cell–cell communications leading to fibrotic and adipogenic lesions. Finally, analysis of gene expression gradients in areas of adjacent muscle and fat, allowed the identification of genes associated with muscle areas committed to becoming fat. © 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 3","pages":"363-380"},"PeriodicalIF":5.2,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809298","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":"Tubal ligation exacerbates ovulation-driven TP53 mutagenesis and p53 signatures by depleting protective menstrual hemoglobin","authors":"Kanchana Subramani,&nbsp;Cheng-Chuan Su,&nbsp;Jen-Hung Wang,&nbsp;Hsuan-Shun Huang,&nbsp;Chun-Shuo Hsu,&nbsp;Pao-Chu Chen,&nbsp;Tang-Yuan Chu","doi":"10.1002/path.70064","DOIUrl":"10.1002/path.70064","url":null,"abstract":"<p>The fallopian tube epithelium (FTE) is the primary tissue of origin for ovarian high-grade serous carcinoma (HGSC), with ovulation implicated as a key risk factor. <i>TP53</i> mutations, a hallmark of HGSC and its precursor lesions, such as p53 signature, are predominantly CG&gt;TA substitutions attributed to cytidine deamination. We previously demonstrated that ovulatory follicular fluid (FF) released reactive oxygen species (ROS), which activate activation-induced cytidine deaminase (AID) and promote <i>TP53</i> mutagenesis in FTE. Here, we demonstrate that hemoglobin (Hb) originating from retrograde menstruation acts as an extracellular ROS scavenger, attenuating AID-mediated <i>TP53</i> deamination in fallopian tube fimbriae, both <i>in vitro</i> and <i>in vivo</i>. Peritoneal fluid from tubal-ligated women exhibited significantly lower Hb, higher ROS, and elevated hypoxanthine phosphoribosyl transferase (<i>HPRT</i>) mutagenic activity compared to nonligated controls (<i>p</i> &lt; 0.004). Histopathological analysis of 206 fallopian tubes from 119 women undergoing opportunistic salpingectomy further revealed a significantly higher frequency of p53 signatures in ligated tubes (0.22 ± 0.64 lesions per fimbria) than in nonligated tubes (0.07 ± 0.31 lesions per fimbria) (<i>p</i> = 0.017). Multivariate analysis identified tubal ligation as the sole reproductive factor independently associated with p53 signatures [odds ratio (OR) = 3.32; 95% CI: 1.15–9.57]. Our findings indicate that retrograde menstrual Hb mitigates ovulation-associated ROS stress, thereby reducing AID-mediated <i>TP53</i> mutagenesis in the FTE. This study uncovers a physiological, protective role for menstruation against ovulatory oxidative damage and its mutagenic consequences, while demonstrating that tubal ligation disrupts this endogenous antioxidant mechanism, resulting in an increased burden of p53 signature lesions. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 3","pages":"337-347"},"PeriodicalIF":5.2,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758598","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":"Multinodular and vacuolating neuronal tumor: molecular genetics and DNA methylation analysis of 12 cases","authors":"Fang Lian,&nbsp;Dan-Dan Wang,&nbsp;Jing Gong,&nbsp;Tao Luo,&nbsp;Lin-Ai Guo,&nbsp;Wei-Min Wang,&nbsp;Ni Chen,&nbsp;Xiao-Hong Yao,&nbsp;Yue-Shan Piao","doi":"10.1002/path.70056","DOIUrl":"10.1002/path.70056","url":null,"abstract":"<p>Multinodular and vacuolating neuronal tumor (MVNT) was recognized as a distinct neuronal tumor entity in the revision of the 2021 World Health Organization (WHO) Classification of Tumors of the CNS. In this study, we retrospectively analyzed 12 surgical cases, two of which exhibited ganglioglioma (GG)-like components. The cohort consisted of eight male and four female patients, with a median age of 31 years (age range: 18–53 years). Seizures were the most common clinical presentation, followed by headache and dizziness. Three patients were incidentally identified during physical examination. Ten tumors were located in the cerebral hemisphere, and the remaining two were found in the cerebellum and thalamus, respectively. Histopathological examination revealed clusters of neuroepithelial cells with large amphophilic vacuolated cytoplasm and eccentrically placed round nuclei containing prominent nucleoli. Immunohistochemically, these vacuolated cells were positive for OLIG2, MAP2, SYN and SOX10, and negative for GFAP and NEUN. DNA sequencing analysis identified no mutations in <i>IDH1</i>, <i>IDH2</i>, <i>BRAF</i> V600E, <i>TERT</i> promoter, or <i>EGFR</i> genes. Among the cohort, three cases harbored <i>FGFR2</i> mutations, and <i>FGFR2</i>::<i>INA</i> gene fusion was detected in both MVNT and GG-like components. Two cases carried <i>BRAF</i> mutation, and one case exhibited <i>MAP2K1</i> mutation. A novel <i>BCAN::NTRK1</i> (exon 12–exon 9) gene fusion was identified in one case. DNA methylation profiling of eight cases revealed that none matched with a known CNS tumor type. Six cases formed a separate methylation cluster, suggesting a potential novel molecular subtype, while the remaining two cases exhibited transcriptional similarities to supratentorial pilocytic astrocytoma and rosette-forming glioneuronal tumor (RGNT), respectively. Postoperatively, all patients remained seizure free with no evidence of tumor progression. Only one patient died 16 months after surgery due to an unrelated traffic accident. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 3","pages":"314-321"},"PeriodicalIF":5.2,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508198","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":"Human induced pluripotent stem cell-derived chimeric antigen receptor-macrophages eradicate IL-13Rα2-positive solid tumors","authors":"Ying Yang,&nbsp;Lujing Wang,&nbsp;Yi Zhang,&nbsp;Shuzhen Lyu,&nbsp;Qianying Ruan,&nbsp;Chao Wang,&nbsp;Feiyue Dou,&nbsp;Gongbo Liang,&nbsp;Guangning Yan,&nbsp;Mengru Wang,&nbsp;Haizhen Fan,&nbsp;Haoyue Qi,&nbsp;Weikai Kong,&nbsp;Haitao Guo,&nbsp;Qing Liu,&nbsp;Wenying Wang,&nbsp;Min Mao,&nbsp;Yuxi Huang,&nbsp;Xinyue Zhou,&nbsp;Jiayu Duan,&nbsp;Wangyang Song,&nbsp;Bangguo Huang,&nbsp;Yuhui Cheng,&nbsp;Lei Zhou,&nbsp;Senlin Xu,&nbsp;Jun Shen,&nbsp;Yi-Fang Ping,&nbsp;Xiu-Wu Bian,&nbsp;Zhicheng He,&nbsp;Yu Shi","doi":"10.1002/path.70063","DOIUrl":"10.1002/path.70063","url":null,"abstract":"<p>Macrophages exhibit extensive tumor infiltration capacity across diverse solid malignancies, establishing macrophage-targeted immunotherapies as an emerging frontier in oncology. Genetic engineering of macrophages using chimeric antigen receptor (CAR) technology − enabling recognition and phagocytosis of neoplastic cells − is emerging as a potential therapeutic strategy against solid tumors. Human induced pluripotent stem cells (iPSCs) provide a renewable platform for the efficient differentiation of functionally competent macrophages. In this study, we engineered human iPSC-derived CAR macrophages (iCAR-M) targeting interleukin-13 receptor subunit alpha 2 (IL-13Rα2). Pan-tumor transcriptomic and immunohistochemical analyses revealed that IL-13Rα2, a tumor-associated antigen, was overexpressed in human glioblastoma (GBM), uterine carcinosarcoma (UCS), and melanoma specimens. <i>In vitro</i> phagocytosis assays revealed target-specific clearance of IL-13Rα2-positive tumor cells by iCAR-M. Intracranial administration of iCAR-M potently suppressed tumor growth, enhanced intratumoral cytotoxic T-cell infiltration, and prolonged the survival of humanized, immunocompetent mice bearing GBM xenografts. The administered iCAR-M maintained phagocytic capacity <i>in vivo</i> and acquired an M1-like pro-inflammatory phenotype. Comprehensive safety assessment revealed no detectable evidence of systemic toxicity or treatment-related neurotoxicity. Collectively, these results demonstrate the potent efficacy and favorable safety profile of iPSC-derived, IL-13Rα2-targeted CAR macrophages, supporting their therapeutic potential against solid tumors. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 3","pages":"322-336"},"PeriodicalIF":5.2,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147687272","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":"Distantly metastatic differentiated thyroid carcinoma is kinase-driven and enriched for DNA repair and DNA methylation gene alterations","authors":"Weimao Kong,&nbsp;Longnv Bao,&nbsp;Jianxia Hu,&nbsp;Guangqi Li,&nbsp;Yixuan Liu,&nbsp;Wenwen Ran,&nbsp;Tingling Zhang,&nbsp;Haiyan Gu,&nbsp;Xinyi Zhang,&nbsp;Meili Wang,&nbsp;Hong Ji,&nbsp;Xuzhang Zong,&nbsp;Yongsheng Zhang,&nbsp;Shouqin Dang,&nbsp;Dong Li,&nbsp;Liangling Fa,&nbsp;Xunzong Yu,&nbsp;Xingzhu Pan,&nbsp;Xueqing Li,&nbsp;Jigang Wang","doi":"10.1002/path.70052","DOIUrl":"10.1002/path.70052","url":null,"abstract":"<p>Although distant metastasis is uncommon in differentiated thyroid carcinoma (DTC), it remains the leading cause of thyroid cancer-related mortality. The genetic landscape of distantly metastatic DTC (DMDTC) has not been well characterized in large cohorts. This study aimed to identify functional genetic alterations in DMDTC and validate their biological significance. We included 78 patients with DMDTC and performed DNA-based next-generation sequencing (NGS) in all cases, followed by RNA-based NGS for fusion gene detection, along with a review of previously reported isolated cases. Plasmids harbouring novel variants, including <i>SPON1</i>::<i>ALK</i> and <i>RFTN1</i>::<i>BRAF</i> fusions, and mutations in <i>PTEN</i> (c.322_345del, c.740del, c.968dup), <i>STK11</i> (c.842C&gt;T, c.1225C&gt;T), and <i>DNMT3A</i> (c.891G&gt;A, c.2312G&gt;A, c.2595A&gt;T, c.2606G&gt;A) were constructed and transfected into TPC-1 and HEK293T cells to investigate downstream signalling. The methylation status of differentially methylated genes (DMGs) associated with <i>DNMT3A</i> mutations was analysed using the Infinium MethylationEPIC v2.0 BeadChip, with several DMGs validated by real-time quantitative PCR. The cohort consisted of 25 males and 53 females, with a mean age of 60.3 years at the diagnosis of metastasis. Histological types included papillary carcinoma (31 cases), follicular carcinoma (44 cases), and oncocytic carcinoma (3 cases). The lung and bone were the most common metastatic sites. Multiple metastases and older age were associated with metastasis-free and overall survival. Genetic alterations involving phosphorylation signalling pathways were identified in 61 cases, among which pathological alterations of DNA damage repair (DDR)-related genes were detected in ten cases. Novel <i>RFTN1</i>::<i>BRAF</i> and <i>SPON1</i>::<i>ALK</i> fusions, along with <i>PTEN</i> (c.740del, c.968dup) and <i>STK11</i> (c.842C&gt;T) mutations, could enhance downstream phosphorylation levels. <i>DNMT3A</i> mutations (c.891G&gt;A, c.2312G&gt;A, c.2595A&gt;T, c.2606G&gt;A) induced genome-wide methylation dysregulation, with altered expression of <i>SLC12A7</i>, <i>FLNC</i>, <i>HMGB2</i>, <i>BNC2</i>, and <i>DAPK1</i>. This study shows that DMDTCs are characterized by dysregulated phosphorylation signalling, accompanied by chromosomal instability and aberrant methylation, thus underscoring DDR gene-targeted therapy as a promising strategy. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 3","pages":"284-296"},"PeriodicalIF":5.2,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508189","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":"Tissue-level heterogeneity in FECD: Descemet's membrane phenotypes and association with TCF4 CTG18.1 expansion†","authors":"Sayo Maeno,&nbsp;Yoshinori Oie,&nbsp;Chifune Kai,&nbsp;Kohji Nishida","doi":"10.1002/path.70057","DOIUrl":"10.1002/path.70057","url":null,"abstract":"<p>Late-onset Fuchs endothelial corneal dystrophy (FECD) is commonly framed as a corneal endothelial disease characterised by guttae accumulation and progressive thickening of Descemet's membrane (DM). However, clinical forms and evolutionary profiles vary widely. Vaitinadapoulé <i>et al</i> systematically analysed as many as 500 keratoplasty-derived DMs from 25 European centres using flat mounts and transmitted light microscopy with structured scoring of extracellular matrix (ECM) lesions. The study revealed five FECD phenotypes and spatially organised lesion patterns and supports multiple pathological phenotypes. Radial organisation emerged as a dominant architectural theme, often accompanied by peripheral striae, with changes evident in both central and peripheral DM. Principal component analysis and unsupervised clustering showed modest separability, while manual classification identified dominant phenotypes with appreciable overlap, suggesting pathological phenotypes arise from a combination of lesion features and organisational patterns. In a genotyped subset, DM architectures differed by <i>TCF4</i> CTG18.1 expansion status, linking tissue architecture to repeat biology. This ECM atlas provides a pathology-anchored framework for FECD heterogeneity and motivates prospective clinical correlation and quantitative image analysis. © 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 3","pages":"262-264"},"PeriodicalIF":5.2,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147626475","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":"Cellular origins and etiological factors for squamous cell carcinoma and related cancer types of the bladder","authors":"Xianbin Su,&nbsp;Xuehui Duan,&nbsp;Shihao Bai,&nbsp;Peipei Su,&nbsp;Jing Xiao,&nbsp;Yi Shi,&nbsp;Die Wu,&nbsp;Qiang Liu,&nbsp;Kun Tao,&nbsp;Bo Han,&nbsp;Jiao-Xiang Wu,&nbsp;Sheng Cheng,&nbsp;Shengqian Ding,&nbsp;Nian Liu,&nbsp;Yanfang Chen,&nbsp;Jingjuan Ren,&nbsp;Shuaihu Yuan,&nbsp;Qinghong Shen,&nbsp;Zihan Yin,&nbsp;Futong Tian,&nbsp;Mengyao Liu,&nbsp;Guoliang Yang","doi":"10.1002/path.70053","DOIUrl":"10.1002/path.70053","url":null,"abstract":"<p>Squamous cell carcinoma (SCC) of the bladder is a rare disease with poor prognosis and limited molecular profiling. Here we present a multi-layer, comparative investigation on bladder SCC and related cancers, namely pure urothelial carcinoma (UC), UC with squamous differentiation, and bladder adenocarcinoma. The mutational signatures of SCC, UC with squamous differentiation, and pure UC imply similar etiologies, with APOBEC-derived signatures found in around a third of samples. SCC and UC with squamous differentiation both highly express basal/squamous markers, different from the luminal profile in UC. We have also dissected the tumor microenvironment and cell type-specific expression in primary tumor and lymph node metastases of SCC at single-cell resolution, and SCC tumor cells also exhibit high expression of basal/squamous markers compared with the luminal feature in UC and adenocarcinoma. Similar mutational signatures present at different contributing fractions, combined with distinct transcriptomic features in various types of bladder cancer, provide an interesting perspective on etiological factors and suggest tumor initiation from potentially different urothelial cell types. The molecular landscape of SCC and related bladder cancers presented in this study improves our understanding of their etiologies and possible cellular origins, and may facilitate future prevention strategies and therapy development. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 3","pages":"297-313"},"PeriodicalIF":5.2,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669337","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":"Endoplasmic reticulum stress and the unfolded protein response in lung diseases: molecular pathways and therapeutic interventions","authors":"Lanlan Song,&nbsp;Yichen Liu,&nbsp;Chen Xu,&nbsp;Yaochen Zhang,&nbsp;Kaiming Xu,&nbsp;Dan Yao,&nbsp;Xiaoying Huang","doi":"10.1002/path.70058","DOIUrl":"10.1002/path.70058","url":null,"abstract":"<p>Endoplasmic reticulum stress (ERS) occurs when the protein-folding capacity of the endoplasmic reticulum (ER) is overwhelmed, triggering the unfolded protein response (UPR) to restore homeostasis. However, severe or persistent ERS can shift the UPR toward pro-inflammatory, apoptotic, and fibrotic signaling, thereby exacerbating tissue injury. The pathogenesis and progression of lung diseases, which involve highly heterogeneous cell populations, are significantly influenced by these mechanisms. Indeed, ERS and UPR activation are now recognized as central players in the pathophysiology of numerous lung diseases. This review examines the impact of dysregulated ERS/UPR signaling across different lung diseases, with a particular focus on its cell-type-specific effects and disease-specific implications. Furthermore, we discuss emerging therapeutic strategies designed to modulate these pathways. A comprehensive understanding of the cell-type-specific outcomes of ERS/UPR is therefore crucial for developing targeted interventions to mitigate or reverse lung disease progression. © 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 3","pages":"268-283"},"PeriodicalIF":5.2,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70058","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669317","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}