The Journal of Pathology最新文献

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SMARCB1-deficient malignant melanocytic uveal tumours: a new neural crest-derived tumour entity with SMARCB1-related germline predisposition
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-01-23 DOI: 10.1002/path.6390
Joanna Cyrta, Julien Masliah-Planchon, Owen Hoare, Riwan Brillet, Mamy Andrianteranagna, Pierre Sohier, Liesbeth Cardoen, Yassine Bouchoucha, Mathilde Filser, Andreia Goncalves, Martial Caly, Paul Fréneaux, Kalliopi Stefanaki, Maria Pefkianaki, Maria Moschovi, Alexandre Matet, Nathalie Cassoux, Livia Lumbroso-Le Rouic, Marion Gauthier-Villars, Marc-Henri Stern, Anne Vincent-Salomon, Manuel Rodrigues, Franck Bourdeaut
{"title":"SMARCB1-deficient malignant melanocytic uveal tumours: a new neural crest-derived tumour entity with SMARCB1-related germline predisposition","authors":"Joanna Cyrta,&nbsp;Julien Masliah-Planchon,&nbsp;Owen Hoare,&nbsp;Riwan Brillet,&nbsp;Mamy Andrianteranagna,&nbsp;Pierre Sohier,&nbsp;Liesbeth Cardoen,&nbsp;Yassine Bouchoucha,&nbsp;Mathilde Filser,&nbsp;Andreia Goncalves,&nbsp;Martial Caly,&nbsp;Paul Fréneaux,&nbsp;Kalliopi Stefanaki,&nbsp;Maria Pefkianaki,&nbsp;Maria Moschovi,&nbsp;Alexandre Matet,&nbsp;Nathalie Cassoux,&nbsp;Livia Lumbroso-Le Rouic,&nbsp;Marion Gauthier-Villars,&nbsp;Marc-Henri Stern,&nbsp;Anne Vincent-Salomon,&nbsp;Manuel Rodrigues,&nbsp;Franck Bourdeaut","doi":"10.1002/path.6390","DOIUrl":"10.1002/path.6390","url":null,"abstract":"<p>Rhabdoid tumours (RT) are an aggressive malignancy affecting &lt;2-year-old infants, characterised by biallelic loss-of-function alterations in SWI/SNF-related BAF chromatin remodelling complex subunit B1 (<i>SMARCB1</i>) in nearly all cases. Germline <i>SMARCB1</i> alterations are found in ~30% of patients and define the RT Predisposition Syndrome type 1 (RTPS1). Uveal melanoma (UVM), the most common primary intraocular cancer in adults, does not harbour <i>SMARCB1</i> alterations. We report two cases of a previously undescribed intraocular malignancy that shared some features with UVM and RT, but was also distinct from these entities. Both female patients, aged 23 and 14 years, underwent enucleation, and the tumours were subjected to comprehensive genomic, DNA methylation, and transcriptomic profiling. Pathological examination showed large, amelanotic intraocular tumours with epithelioid features, expressing melanocytic markers [S100P, SOX10, Melan-A, PMEL (HMB45), TYR] as seen using immunohistochemistry (IHC), but with little or no melanin production. Both tumours harboured biallelic loss-of-function <i>SMARCB1</i> alterations, associated with loss of SMARCB1 (BAF47/INI1) expression on IHC. Their genomic profiles were atypical both for UVM and for RT, and no pathogenic variants were found in other genes tested, including those recurrently altered in UVM. In both patients, a germline <i>SMARCB1</i> variant was found. However, there was no relevant family history of cancer. Transcriptome and methylome profiling suggested that these tumours were distinct from RT, UVM, and skin melanomas. RNAseq confirmed expression of early and late genes related to melanocytic differentiation. The first patient died of metastatic disease 16 months after diagnosis, the second was disease-free 10 months after completion of treatment. In summary, we report two cases of a previously undescribed, aggressive <i>SMARCB1</i>-deficient intraocular malignancy with melanocytic differentiation, which occurs in young patients, is distinct from UVM and RT, and expands the RTPS1 spectrum. © 2025 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":"265 3","pages":"357-371"},"PeriodicalIF":5.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6390","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031835","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}
引用次数: 0
C1GALT1 expression predicts poor survival in osteosarcoma and is crucial for ABCC1 transporter-mediated doxorubicin resistance
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-01-22 DOI: 10.1002/path.6384
Chun-Wei Liu, Jing-Hui Huang, Hsiu-Hao Chang, Chia-Hua Chen, Yi-Huan Tsai, Wei-Li Chen, Jung-An Lin, Hsiu-Ling Chang, Cheng-Chang Chen, Mei-Chun Lin, Min-Chuan Huang, Neng-Yu Lin
{"title":"C1GALT1 expression predicts poor survival in osteosarcoma and is crucial for ABCC1 transporter-mediated doxorubicin resistance","authors":"Chun-Wei Liu,&nbsp;Jing-Hui Huang,&nbsp;Hsiu-Hao Chang,&nbsp;Chia-Hua Chen,&nbsp;Yi-Huan Tsai,&nbsp;Wei-Li Chen,&nbsp;Jung-An Lin,&nbsp;Hsiu-Ling Chang,&nbsp;Cheng-Chang Chen,&nbsp;Mei-Chun Lin,&nbsp;Min-Chuan Huang,&nbsp;Neng-Yu Lin","doi":"10.1002/path.6384","DOIUrl":"10.1002/path.6384","url":null,"abstract":"<p>Osteosarcoma is an aggressive bone malignancy with a high propensity for drug resistance and metastasis, leading to poor clinical outcomes. This study investigates the role of core 1 β1,3-galactosyltransferase 1 (C1GALT1) in osteosarcoma, focusing on its implications in chemoresistance. Our findings reveal that high expression of C1GALT1 is associated with advanced stages, adverse overall survival, and increased recurrence rates. Elevated levels of C1GALT1 were observed in doxorubicin-selected osteosarcoma cells, where its suppression significantly promoted doxorubicin-induced apoptosis and reduced drug efflux. Pharmacological inhibition of C1GALT1 using itraconazole replicated these effects, suggesting a potential therapeutic strategy to overcome chemoresistance. Additionally, we identified the involvement of the ATP-binding cassette (ABC) transporter ABCC1 in the drug-resistance phenotype mediated by C1GALT1. C1GALT1-mediated O-glycan changes were found to influence the cell-surface targeting and lysosomal degradation of ABCC1, thereby modulating its efflux capacity. <i>In vitro</i> and <i>in vivo</i> studies confirmed that C1GALT1 impacts ABCC1 expression and function, further supporting its role in osteosarcoma chemoresistance. These results highlight the clinical relevance of C1GALT1 as a biomarker for prognosis and a potential therapeutic target for osteosarcoma. © 2025 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":"265 3","pages":"289-301"},"PeriodicalIF":5.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6384","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021414","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}
引用次数: 0
CHIT1 regulates the neuroinflammation and phagocytosis of microglia and suppresses Aβ plaque deposition in Alzheimer's disease CHIT1调节阿尔茨海默病小胶质细胞的神经炎症和吞噬,抑制Aβ斑块沉积。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-01-20 DOI: 10.1002/path.6387
Shiyun Yuan, Fuxin Zhong, Tianchi Wan, Zhangjin Qin, Lihua Chen, Dianxia Xing, Wenbo Zhang, Wuhan Yu, Lihong Huang, Jiaqi Song, Weihua Yu, Yang Lü
{"title":"CHIT1 regulates the neuroinflammation and phagocytosis of microglia and suppresses Aβ plaque deposition in Alzheimer's disease","authors":"Shiyun Yuan,&nbsp;Fuxin Zhong,&nbsp;Tianchi Wan,&nbsp;Zhangjin Qin,&nbsp;Lihua Chen,&nbsp;Dianxia Xing,&nbsp;Wenbo Zhang,&nbsp;Wuhan Yu,&nbsp;Lihong Huang,&nbsp;Jiaqi Song,&nbsp;Weihua Yu,&nbsp;Yang Lü","doi":"10.1002/path.6387","DOIUrl":"10.1002/path.6387","url":null,"abstract":"<p>Chitinase 1 (CHIT1), as a chitin-specific hydrolase, significantly influences the progression of Alzheimer's disease (AD) through microglia-associated inflammation and amyloid beta (Aβ) plaque accumulation. However, the precise mechanism of CHIT1 action in AD remains uncertain. The effects of CHIT1 on cerebral blood flow (CBF), hippocampal volume, and cognitive function were investigated in APP/PS1 mice. Protein alterations resulting from CHIT1 overexpression were analyzed using four-dimensional (4D) label-free quantitative (LFQ) protein spectrometry. Additionally, the influence of CHIT1 on microglial electrophysiology was assessed using patch clamp measurements, and its effects on neuroinflammation, phagocytosis, microglia migration, and neuronal apoptosis under AD-like conditions were examined using the cell lines N9, BV-2, and HT-22. CHIT1 ameliorated hippocampal atrophy, hypoperfusion, and cognitive function deficits in the APP/PS1 mouse. CHIT1 regulates microglial function and neuronal protection through its interactions in AD. Increased levels of CHIT1/IDH1 contributed to an anti-inflammatory phenotype in microglia via the Ca2<sup>+</sup>-activated K+ channel, enhanced microglial phagocytosis, and promoted Aβ clearance. Conversely, knocking down IDH1 reduced the secretion of anti-inflammatory agents and increased the production of inflammatory factors, as well as diminishing the expression of phagocytic factors and inhibiting Aβ endocytosis. Moreover, CHIT1 reduced neuronal apoptosis by diminishing the expression of apoptotic factors. However, IDH1 knockdown abrogated the protective effect of CHIT1 on neurons. CHIT1 exerts a protective role in AD pathogenesis through its interaction with IDH1. The CHIT1/IDH1 pathway promotes Aβ clearance via a shift in microglia toward an anti-inflammatory state and prevents neuronal apoptosis and dysfunction caused by Aβ toxicity. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 3","pages":"330-341"},"PeriodicalIF":5.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997165","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}
引用次数: 0
Oronasal mucosal melanoma is defined by two transcriptional subtypes in humans and dogs with implications for diagnosis and therapy 口鼻黏膜黑色素瘤由人类和狗的两种转录亚型定义,对诊断和治疗具有指导意义。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-01-19 DOI: 10.1002/path.6377
Kelly L Bowlt Blacklock, Kevin Donnelly, Yuting Lu, Jorge del Pozo, Laura Glendinning, Gerry Polton, Laura Selmic, Jean-Benoit Tanis, David Killick, Maciej Parys, Joanna S Morris, Inge Breathnach, Stefano Zago, Sara M Gould, Darren J Shaw, Michael S Tivers, Davide Malucelli, Ana Marques, Katarzyna Purzycka, Matteo Cantatore, Marie E Mathers, Mark Stares, Alison Meynert, E Elizabeth Patton
{"title":"Oronasal mucosal melanoma is defined by two transcriptional subtypes in humans and dogs with implications for diagnosis and therapy","authors":"Kelly L Bowlt Blacklock,&nbsp;Kevin Donnelly,&nbsp;Yuting Lu,&nbsp;Jorge del Pozo,&nbsp;Laura Glendinning,&nbsp;Gerry Polton,&nbsp;Laura Selmic,&nbsp;Jean-Benoit Tanis,&nbsp;David Killick,&nbsp;Maciej Parys,&nbsp;Joanna S Morris,&nbsp;Inge Breathnach,&nbsp;Stefano Zago,&nbsp;Sara M Gould,&nbsp;Darren J Shaw,&nbsp;Michael S Tivers,&nbsp;Davide Malucelli,&nbsp;Ana Marques,&nbsp;Katarzyna Purzycka,&nbsp;Matteo Cantatore,&nbsp;Marie E Mathers,&nbsp;Mark Stares,&nbsp;Alison Meynert,&nbsp;E Elizabeth Patton","doi":"10.1002/path.6377","DOIUrl":"10.1002/path.6377","url":null,"abstract":"<p>Mucosal melanoma is a rare melanoma subtype associated with a poor prognosis and limited existing therapeutic interventions, in part due to a lack of actionable targets and translational animal models for preclinical trials. Comprehensive data on this tumour type are scarce, and existing data often overlooks the importance of the anatomical site of origin. We evaluated human and canine oronasal mucosal melanoma (OMM) to determine whether the common canine disease could inform the rare human equivalent. Using a human and canine primary OMM cohort of treatment-naive archival tissue, alongside clinicopathological data, we obtained transcriptomic, immunohistochemical, and microbiome data from both species. We defined the transcriptomic landscape in both species and linked our findings to immunohistochemical, microbiome, and clinical data. Human and dog OMM stratified into two distinctive transcriptional groups, which we defined using a species-independent 41-gene signature. These two subgroups are termed CTLA4-high and MET-high and indicate actionable targets for OMM patients. To guide clinical decision-making, we developed immunohistochemical diagnostic tools that distinguish between transcriptomic subgroups. We found that OMM had conserved transcriptomic subtypes and biological similarity between human and canine OMM, with significant implications for patient classification, treatment, and clinical trial design. © 2025 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":"265 3","pages":"245-259"},"PeriodicalIF":5.6,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6377","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997166","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}
引用次数: 0
Recombinant Klotho administration after myocardial infarction reduces ischaemic injury and arrhythmias by blocking intracellular calcium mishandling and CaMKII activation 心肌梗死后重组Klotho通过阻断细胞内钙处理不当和CaMKII激活减少缺血损伤和心律失常。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-01-15 DOI: 10.1002/path.6388
Sara Vázquez-Sánchez, Ana Blasco, Pablo Fernández-Corredoira, Paula Cantolla, Elisa Mercado-García, Elena Rodríguez-Sánchez, Laura González-Lafuente, Jonay Poveda, Daniel González-Moreno, Andrea Matutano, Sonia Peribañez, Inés García-Consuegra, Massimo Volpe, María Fernández-Velasco, Luis M. Ruilope, Gema Ruiz-Hurtado
{"title":"Recombinant Klotho administration after myocardial infarction reduces ischaemic injury and arrhythmias by blocking intracellular calcium mishandling and CaMKII activation","authors":"Sara Vázquez-Sánchez,&nbsp;Ana Blasco,&nbsp;Pablo Fernández-Corredoira,&nbsp;Paula Cantolla,&nbsp;Elisa Mercado-García,&nbsp;Elena Rodríguez-Sánchez,&nbsp;Laura González-Lafuente,&nbsp;Jonay Poveda,&nbsp;Daniel González-Moreno,&nbsp;Andrea Matutano,&nbsp;Sonia Peribañez,&nbsp;Inés García-Consuegra,&nbsp;Massimo Volpe,&nbsp;María Fernández-Velasco,&nbsp;Luis M. Ruilope,&nbsp;Gema Ruiz-Hurtado","doi":"10.1002/path.6388","DOIUrl":"10.1002/path.6388","url":null,"abstract":"<p>Ischaemic heart disease (IHD) remains a major cause of death and morbidity. Klotho is a well-known anti-ageing factor with relevant cardioprotective actions, at least when renal dysfunction is present, but its actions are much less known when renal function is preserved. This study investigated Klotho as a biomarker and potential novel treatment of IHD-associated complications after myocardial infarction (MI) under preserved renal function. Association between circulating Klotho levels and cardiac injury was investigated in patients after ST-elevation MI (STEMI). Biochemical, <i>in vivo</i> and <i>in vitro</i> cardiac function and histological and molecular studies were performed to determine the effect of recombinant Klotho in the failing hearts of mice after MI. We demonstrated that STEMI patients showed lower systemic Klotho levels, with the lowest Klotho tertile in those patients with higher N-terminal pro B-type natriuretic peptide (NT-proBNP) levels. Mice also showed a decrease in systemic Klotho levels after MI induction. Furthermore, recombinant Klotho administration in mice reduced infarct area and attenuated cardiac hypertrophy and fibrosis. We also demonstrated that Klotho treatment prevented reduction in ejection fraction and MI-related ECG changes, including prolonged QRS, JT, QTc, and T<sub>peak</sub>T<sub>end</sub> intervals and premature ventricular contractions. In adult mouse cardiomyocytes, Klotho treatment restricted systolic calcium (Ca<sup>2+</sup>) release and cell shortening disturbances after MI. Klotho prevented increased diastolic Ca<sup>2+</sup> leak and pro-arrhythmogenic events in PMI mice by blocking activation of the Ca<sup>2+</sup>/calmodulin-dependent kinase type II (CaMKII) pathway, preventing ryanodine receptor type 2 (RyR<sub>2</sub>) hyperphosphorylation. In conclusion, Klotho supplementation protected against functional and structural cardiac remodelling and ameliorated ventricular arrhythmic events by preventing intracardiomyocyte Ca<sup>2+</sup> mishandling in mice following MI. These data uncover a new cardioprotective role of Klotho, emerging as a biomarker of ventricular injury and potential treatment for patients after MI. © 2025 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":"265 3","pages":"342-356"},"PeriodicalIF":5.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6388","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997167","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}
引用次数: 0
DNA methylation patterns are influenced by Pax3::Foxo1 expression and developmental lineage in rhabdomyosarcoma tumours forming in genetically engineered mouse models DNA甲基化模式受Pax3::Foxo1表达和基因工程小鼠横纹肌肉瘤肿瘤形成的发育谱系的影响。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-01-15 DOI: 10.1002/path.6386
Wenyue Sun, Stephen M Hewitt, Hollis Wright, Charles Keller, Frederic G Barr
{"title":"DNA methylation patterns are influenced by Pax3::Foxo1 expression and developmental lineage in rhabdomyosarcoma tumours forming in genetically engineered mouse models","authors":"Wenyue Sun,&nbsp;Stephen M Hewitt,&nbsp;Hollis Wright,&nbsp;Charles Keller,&nbsp;Frederic G Barr","doi":"10.1002/path.6386","DOIUrl":"10.1002/path.6386","url":null,"abstract":"<p>Rhabdomyosarcoma (RMS) is a family of phenotypically myogenic paediatric cancers consisting of two major subtypes: fusion-positive (FP) RMS, most commonly involving the <i>PAX3</i>::<i>FOXO1</i> fusion gene, formed by the fusion of paired box 3 (<i>PAX3</i>) and forkhead box O1 (<i>FOXO1</i>) genes, and fusion-negative (FN) RMS, lacking these gene fusions. In humans, DNA methylation patterns distinguish these two subtypes as well as mutation-associated subsets within these subtypes. To investigate the biological factors responsible for these methylation differences, we profiled DNA methylation in RMS tumours derived from genetically engineered mouse models (GEMMs) in which various driver mutations were introduced into different myogenic lineages. Our unsupervised analyses of DNA methylation patterns in these GEMM tumours yielded two major clusters, corresponding to high and no/low expression of <i>Pax3</i>::<i>Foxo1</i>, which mirrored the results for human FP and FN RMS tumours. Two distinct methylation-defined subsets were found for GEMM RMS tumours with no/low <i>Pax3</i>::<i>Foxo1</i> expression: one subset enriched in <i>Pax7</i> lineage tumours and a second subset enriched in myogenic factor 5 (<i>Myf5</i>) lineage tumours. Integrative analysis of DNA methylation and transcriptomic data in mouse and human RMS revealed a common group of differentially methylated and differentially expressed genes, highlighting a conserved set of genes functioning in both human RMS models and GEMMs of RMS. In conclusion, these studies provide insight into the roles of oncogenic fusion proteins and developmental lineages in establishing DNA methylation patterns in FP and FN RMS respectively. © 2025 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. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 3","pages":"316-329"},"PeriodicalIF":5.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6386","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982131","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}
引用次数: 0
Silencing GRHL3 promotes multiple organ distant metastasis of lung squamous cell carcinoma cells by enhancing SOX2 stability via SIRT1 沉默GRHL3通过SIRT1增强SOX2稳定性促进肺鳞癌多器官远处转移。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-01-13 DOI: 10.1002/path.6385
Zhanzhan Li, Baishuang Yang, Meihua Long, Jiarong Chen, Yaofeng Zhi, Ronggang Li, Lixue Cao, Shasha Yang, Jingyi Sun, Zijie Meng, Wanting Wu, Yanyang Mai, Xin Zhang, Yanming Huang, Qiong Chen, Aibin Liu
{"title":"Silencing GRHL3 promotes multiple organ distant metastasis of lung squamous cell carcinoma cells by enhancing SOX2 stability via SIRT1","authors":"Zhanzhan Li,&nbsp;Baishuang Yang,&nbsp;Meihua Long,&nbsp;Jiarong Chen,&nbsp;Yaofeng Zhi,&nbsp;Ronggang Li,&nbsp;Lixue Cao,&nbsp;Shasha Yang,&nbsp;Jingyi Sun,&nbsp;Zijie Meng,&nbsp;Wanting Wu,&nbsp;Yanyang Mai,&nbsp;Xin Zhang,&nbsp;Yanming Huang,&nbsp;Qiong Chen,&nbsp;Aibin Liu","doi":"10.1002/path.6385","DOIUrl":"10.1002/path.6385","url":null,"abstract":"<p>Aberrant expression of grainyhead-like transcription factor 3 (GRHL3) has been extensively reported in the development and progression of several squamous cell carcinomas, such as cutaneous, head and neck, and esophageal squamous cell carcinoma. However, the clinical significance and biological roles of GRHL3 in lung squamous cell (LUSC) carcinoma are largely unclear. Herein, we report that GRHL3 was significantly upregulated in lung squamous epithelium of LUSC tissues, bronchiole, and bronchus. Moreover, expression levels of GRHL3 were decreased with the advance of pathological grade, and low GRHL3 level presented poor overall survival and short progression-free and distant metastasis-free survival in LUSC patients but had no prognostic significance in LUAD patients. Functional experiments <i>in vivo</i> showed that downregulating GRHL3 promoted not only lung colonization and growth but also multiple organ distant metastasis of LUSC cells, including bone, brain, and liver. Moreover, silencing GRHL3 promoted anoikis resistance and cancer stem cell (CSCs) characteristics of LUSC cells <i>in vitro</i>. Mechanistically, silencing GRHL3 stabilized SOX2 via SIRT1-mediated decreasing acetylation and subsequent ubiquitination-dependent degradation in LUSC cells. Thus, in-depth understanding of the underlying mechanism of GRHL3 in the progression of LUSC will facilitate the development of prognostic biomarker and therapeutic avenues against LUSC, which will present favorable prospects in improving outcomes of LUSC patients. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 3","pages":"302-315"},"PeriodicalIF":5.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968885","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}
引用次数: 0
Dynamic change of polarity in spread through air spaces of pulmonary malignancies 肺部恶性肿瘤通过空气空间扩散时极性的动态变化。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-01-13 DOI: 10.1002/path.6382
Yoshiaki Matsuura, Kunishige Onuma, Roberto Coppo, Hiroyuki Uematsu, Jumpei Kondo, Aya Miyagawa-Hayashino, Naoko Takeda-Miyata, Kenji Kameyama, Tatsuo Furuya, Satoru Okada, Masanori Shimomura, Masayoshi Inoue, Masahiro Inoue
{"title":"Dynamic change of polarity in spread through air spaces of pulmonary malignancies","authors":"Yoshiaki Matsuura,&nbsp;Kunishige Onuma,&nbsp;Roberto Coppo,&nbsp;Hiroyuki Uematsu,&nbsp;Jumpei Kondo,&nbsp;Aya Miyagawa-Hayashino,&nbsp;Naoko Takeda-Miyata,&nbsp;Kenji Kameyama,&nbsp;Tatsuo Furuya,&nbsp;Satoru Okada,&nbsp;Masanori Shimomura,&nbsp;Masayoshi Inoue,&nbsp;Masahiro Inoue","doi":"10.1002/path.6382","DOIUrl":"10.1002/path.6382","url":null,"abstract":"<p>Spread through air spaces (STAS) is a histological finding of lung tumours where tumour cells exist within the air space of the lung parenchyma beyond the margin of the main tumour. Although STAS is an important prognostic factor, the pathobiology of STAS remains unclear. Here, we investigated the mechanism of STAS by analysing the relationship between STAS and polarity switching <i>in vivo</i> and <i>in vitro</i>. Histopathological analysis revealed that apical membranes were observed outside the STAS lesions around colorectal cancer (CRC) lung metastases and lung adenocarcinomas. When apical-out CRC organoids were administered intratracheally to mice, the organoids had greater metastatic potential than did single cells. To investigate the pathobiology of STAS, we established an <i>in vitro</i> model of STAS in which CRC or lung cancer organoids were co-cultured with 2D-cultured mouse airway epithelial organoids (2D-MAOs). Adhesion of cancer organoids to 2D-MAOs was much less than to type I collagen or endothelial cells, suggesting a protective role of the airway epithelium against adhesion. Loss of the apical membrane of CRC organoids at the contact surface with 2D-MAOs after adhesion was responsible for establishing adhesion. When airway epithelium was stimulated by transforming growth factor beta 1 (TGF-β1), adhesion of CRC organoids was enhanced. Among TGF-β1-induced genes in airway epithelium, follistatin-like protein 1 (FSTL1) increased CRC organoid adhesion by promoting loss of the apical membrane. These results suggested that TGF-β1-induced FSTL1 may promote metastatic progression of STAS by altering the polarity status. Elucidating the mechanism of STAS could contribute to the improvement of survival in patients with pulmonary malignancies associated with STAS. © 2025 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":"265 3","pages":"260-273"},"PeriodicalIF":5.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6382","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968884","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}
引用次数: 0
Computational pathology applied to clinical colorectal cancer cohorts identifies immune and endothelial cell spatial patterns predictive of outcome 计算病理学应用于临床结直肠癌队列确定预测结果的免疫和内皮细胞空间模式。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-01-09 DOI: 10.1002/path.6378
Nicholas Trahearn, Chirine Sakr, Abhirup Banerjee, Seung Hyun Lee, Ann-Marie Baker, Hemant M Kocher, Valentina Angerilli, Federica Morano, Francesca Bergamo, Giulia Maddalena, Rossana Intini, Chiara Cremolini, Giulio Caravagna, Trevor Graham, Filippo Pietrantonio, Sara Lonardi, Matteo Fassan, Andrea Sottoriva
{"title":"Computational pathology applied to clinical colorectal cancer cohorts identifies immune and endothelial cell spatial patterns predictive of outcome","authors":"Nicholas Trahearn,&nbsp;Chirine Sakr,&nbsp;Abhirup Banerjee,&nbsp;Seung Hyun Lee,&nbsp;Ann-Marie Baker,&nbsp;Hemant M Kocher,&nbsp;Valentina Angerilli,&nbsp;Federica Morano,&nbsp;Francesca Bergamo,&nbsp;Giulia Maddalena,&nbsp;Rossana Intini,&nbsp;Chiara Cremolini,&nbsp;Giulio Caravagna,&nbsp;Trevor Graham,&nbsp;Filippo Pietrantonio,&nbsp;Sara Lonardi,&nbsp;Matteo Fassan,&nbsp;Andrea Sottoriva","doi":"10.1002/path.6378","DOIUrl":"10.1002/path.6378","url":null,"abstract":"<p>Colorectal cancer (CRC) is a histologically heterogeneous disease with variable clinical outcome. The role the tumour microenvironment (TME) plays in determining tumour progression is complex and not fully understood. To improve our understanding, it is critical that the TME is studied systematically within clinically annotated patient cohorts with long-term follow-up. Here we studied the TME in three clinical cohorts of metastatic CRC with diverse molecular subtype and treatment history. The MISSONI cohort included cases with microsatellite instability that received immunotherapy (<i>n</i> = 59, 24 months median follow-up). The BRAF cohort included BRAF V600E mutant microsatellite stable (MSS) cancers (<i>n</i> = 141, 24 months median follow-up). The VALENTINO cohort included RAS/RAF WT MSS cases who received chemotherapy and anti-EGFR therapy (<i>n</i> = 175, 32 months median follow-up). Using a Deep learning cell classifier, trained upon &gt;38,000 pathologist annotations, to detect eight cell types within H&amp;E-stained sections of CRC, we quantified the spatial tissue organisation and colocalisation of cell types across these cohorts. We found that the ratio of infiltrating endothelial cells to cancer cells, a possible marker of vascular invasion, was an independent predictor of progression-free survival (PFS) in the BRAF+MISSONI cohort (<i>p</i> = 0.033, HR = 1.44, CI = 1.029–2.01). In the VALENTINO cohort, this pattern was also an independent PFS predictor in <i>TP53</i> mutant patients (<i>p</i> = 0.009, HR = 0.59, CI = 0.40–0.88). Tumour-infiltrating lymphocytes were an independent predictor of PFS in BRAF+MISSONI (<i>p</i> = 0.016, HR = 0.36, CI = 0.153–0.83). Elevated tumour-infiltrating macrophages were predictive of improved PFS in the MISSONI cohort (<i>p</i> = 0.031). We validated our cell classification using highly multiplexed immunofluorescence for 17 markers applied to the same sections that were analysed by the classifier (<i>n</i> = 26 cases). These findings uncovered important microenvironmental factors that underpin treatment response across and within CRC molecular subtypes, while providing an atlas of the distribution of 180 million cells in 375 clinically annotated CRC patients. © 2025 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":"265 2","pages":"198-210"},"PeriodicalIF":5.6,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942101","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}
引用次数: 0
Jeremy Jass Prize for Research Excellence in Pathology 2023
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-01-09 DOI: 10.1002/path.6389
{"title":"Jeremy Jass Prize for Research Excellence in Pathology 2023","authors":"","doi":"10.1002/path.6389","DOIUrl":"https://doi.org/10.1002/path.6389","url":null,"abstract":"<p>Every year, the Editorial Team of <i>The Journal of Pathology</i> awards the <b>Jeremy Jass Prize for Research Excellence</b> to the paper published in the previous calendar year that is deemed to have the highest scientific calibre. The selection process is always challenging due to the consistently high standards of the papers published in the journal.</p><p>The paper selected for the Jass Prize for the calendar year 2023 is:</p><p>Jinglin Zhang†, Bonan Chen†, Hui Li†, Yifei Wang, Xiaoli Liu, Kit Yee Wong, Wai Nok Chan, Aden KY Chan, Alvin HK Cheung, Kam Tong Leung, Yujuan Dong, Yi Pan, Huixing Ke, Li Liang, Zhaocai Zhou, Jianyong Xiao, Chi Chun Wong, William KK Wu, Alfred SL Cheng, Brigette BY Ma, Jun Yu, Kwok Wai Lo, Wei Kang* and Ka Fai To*. Cancer-associated fibroblasts potentiate colorectal cancer progression by crosstalk of the IGF2–IGF1R and Hippo–YAP1 signaling pathways. <i>J Pathol</i> 2023; <b>259:</b> 205–219. DOI: 10.1002/path.6033</p><p>† <i>Equal contributions</i>, * <i>Corresponding authors</i>.</p><p>We offer our congratulations to the authors, who are shown in Figure 1. The paper is available with Free Access at https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6033</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 2","pages":"244"},"PeriodicalIF":5.6,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6389","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143113823","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}
引用次数: 0
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