The Journal of Pathology最新文献

{"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}

{"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}

{"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}

{"title":"Loss of Mist1 alters the characteristics of Paneth cells and impacts the function of intestinal stem cells in physiological conditions and after radiation injury","authors":"Yujun Huang,&nbsp;Siyu Tu,&nbsp;Zhenni Xu,&nbsp;Lu Xu,&nbsp;Xi Wang,&nbsp;Hefei Tian,&nbsp;Qican He,&nbsp;Lingxiao Huang,&nbsp;Xudan Lei,&nbsp;Shubin Wang,&nbsp;Mingyue Qu,&nbsp;Dengqun Liu","doi":"10.1002/path.6360","DOIUrl":"10.1002/path.6360","url":null,"abstract":"<p>Intestinal stem cells (ISCs) and Paneth cells (PCs) reside at the bottom of the crypts of Lieberkühn in the small intestine. Recent studies have shown that the transcription factor Mist1, also named BHLHA15, plays an important role in the maturation of PCs. Since there is an intimate interaction between PCs and ISCs, we speculated that the loss of Mist1 could impact these two neighboring cell types. Here, we report that mice lacking Mist1 had fewer but larger PCs with shrunken secretory granules, accompanied by an increase in goblet cells and tuft cells. Mist1 loss significantly decreased the number of proliferative crypt cells, especially columnar basal cells (CBCs). In addition, Mist1-deficient enteroids needed supplemental Wnt3a to support their growth. Results from RNA sequencing (RNA-seq) demonstrated an apparent deficiency of innate immunity in Mist1-knockout mice. Intriguingly, Mist1 loss increased the survival rate of mice subjected to whole abdominal irradiation (WAI). Moreover, radiation injury was ameliorated in Mist1-knockout mice compared with their wild-type littermates based on histological analysis and enteroid culture, which might be a consequence of increased contents of the endoplasmic reticulum (ER) and the increased activity of mTORC1 in Paneth cells. In summary, our data uncover that Mist1 plays an important functional role in PCs and regulates the maintenance of ISCs and their response to radiation injury. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 2","pages":"132-145"},"PeriodicalIF":5.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918726","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":"Primary thyroid B-cell lymphoma: molecular insights into its clonal evolution and relapse","authors":"Maria-Myrsini Tzioni,&nbsp;Natsuko Watanabe,&nbsp;Zi Chen,&nbsp;Fangtian Wu,&nbsp;Ewelina Madej,&nbsp;Jasmine Makker,&nbsp;Sarah Guo,&nbsp;Ayoma D Attygalle,&nbsp;Andrew Wotherspoon,&nbsp;Kiminori Sugino,&nbsp;Koichi Ito,&nbsp;Ming-Qing Du","doi":"10.1002/path.6380","DOIUrl":"10.1002/path.6380","url":null,"abstract":"<p>Primary thyroid lymphomas comprise largely extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL) and diffuse large B-cell lymphoma (DLBCL), followed by follicular lymphoma (FL). They commonly develop from a background of Hashimoto's thyroiditis (HT), where dysregulated immune responses trigger autoreactive infiltrates and drive clonal B-cell evolution. To understand how these lymphomas and their relapse evolve, we investigated 10 cases by mutation profiling, including five with metachronous lymphomas [primary lymphoma (EMZL = 4, DLBCL = 1) with local relapse (EMZL = 3, DLBCL = 2)], one composite EMZL and Epstein–Barr virus (EBV)-positive DLBCL, and four lymphomas (EMZL = 3, FL = 1) with prior or subsequent biopsy showing HT. In four cases with metachronous lymphomas, both common and distinct variants were seen in the paired lesions, indicating their divergent evolution from clonally related lymphoma precursor (CLP) cells. In the remaining case with metachronous lymphomas, the relapsed lesion was progressed from the initial lymphoma. In the case with composite lymphoma, the EBV-positive DLBCL was transformed from EMZL. Finally, in the four cases with paired lymphoma and HT biopsies, two showed shared mutations between the paired lesions, indicating involvement and divergent evolution from CLP cells. Thyroid lymphoma relapse may frequently develop via divergent evolution from a CLP cell, which is likely premalignant. © 2024 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":"123-131"},"PeriodicalIF":5.6,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890779","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":"Tumour purity assessment with deep learning in colorectal cancer and impact on molecular analysis","authors":"Lydia A Schoenpflug,&nbsp;Aikaterini Chatzipli,&nbsp;Korsuk Sirinukunwattana,&nbsp;Susan Richman,&nbsp;Andrew Blake,&nbsp;James Robineau,&nbsp;Kirsten D Mertz,&nbsp;Clare Verrill,&nbsp;Simon J Leedham,&nbsp;Claire Hardy,&nbsp;Celina Whalley,&nbsp;Keara Redmond,&nbsp;Philip Dunne,&nbsp;Steven Walker,&nbsp;Andrew D Beggs,&nbsp;Ultan McDermott,&nbsp;Graeme I Murray,&nbsp;Leslie M Samuel,&nbsp;Matthew Seymour,&nbsp;Ian Tomlinson,&nbsp;Philip Quirke,&nbsp;S:CORT consortium,&nbsp;Jens Rittscher,&nbsp;Tim Maughan,&nbsp;Enric Domingo,&nbsp;Viktor H Koelzer","doi":"10.1002/path.6376","DOIUrl":"10.1002/path.6376","url":null,"abstract":"<p>Tumour content plays a pivotal role in directing the bioinformatic analysis of molecular profiles such as copy number variation (CNV). In clinical application, tumour purity estimation (TPE) is achieved either through visual pathological review [conventional pathology (CP)] or the deconvolution of molecular data. While CP provides a direct measurement, it demonstrates modest reproducibility and lacks standardisation. Conversely, deconvolution methods offer an indirect assessment with uncertain accuracy, underscoring the necessity for innovative approaches. SoftCTM is an open-source, multiorgan deep-learning (DL) model for the detection of tumour and non-tumour cells in H&amp;E-stained slides, developed within the Overlapped Cell on Tissue Dataset for Histopathology (OCELOT) Challenge 2023. Here, using three large multicentre colorectal cancer (CRC) cohorts (<i>N</i> = 1,097 patients) with digital pathology and multi-omic data, we compare the utility and accuracy of TPE with SoftCTM versus CP and bioinformatic deconvolution methods (RNA expression, DNA methylation) for downstream molecular analysis, including CNV profiling. SoftCTM showed technical repeatability when applied twice on the same slide (<i>r</i> = 1.0) and excellent correlations in paired H&amp;E slides (<i>r</i> &gt; 0.9). TPEs profiled by SoftCTM correlated highly with RNA expression (<i>r</i> = 0.59) and DNA methylation (<i>r</i> = 0.40), while TPEs by CP showed a lower correlation with RNA expression (<i>r</i> = 0.41) and DNA methylation (<i>r</i> = 0.29). We show that CP and deconvolution methods respectively underestimate and overestimate tumour content compared to SoftCTM, resulting in 6–13% differing CNV calls. In summary, TPE with SoftCTM enables reproducibility, automation, and standardisation at single-cell resolution. SoftCTM estimates (<i>M</i> = 58.9%, SD ±16.3%) reconcile the overestimation by molecular data extrapolation (RNA expression: <i>M</i> = 79.2%, SD ±10.5, DNA methylation: <i>M</i> = 62.7%, SD ±11.8%) and underestimation by CP (<i>M</i> = 35.9%, SD ±13.1%), providing a more reliable middle ground. A fully integrated computational pathology solution could therefore be used to improve downstream molecular analyses for research and clinics. © 2024 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":"184-197"},"PeriodicalIF":5.6,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876017","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":"Characterisation of GPR17-expressing oligodendrocyte precursors in human ischaemic lesions and correlation with reactive glial responses","authors":"Stefano Raffaele,&nbsp;Bettina Hjelm Clausen,&nbsp;Francesca Carolina Mannella,&nbsp;Martin Wirenfeldt,&nbsp;Davide Marangon,&nbsp;Sarah Boe Tidgen,&nbsp;Silvia Corradini,&nbsp;Kirsten Madsen,&nbsp;Davide Lecca,&nbsp;Maria Pia Abbracchio,&nbsp;Kate Lykke Lambertsen,&nbsp;Marta Fumagalli","doi":"10.1002/path.6381","DOIUrl":"10.1002/path.6381","url":null,"abstract":"<p>White matter damage and subsequent demyelination significantly contribute to long-term functional impairment after ischaemic stroke. Identifying novel pharmacological targets to restore myelin integrity by promoting the maturation of oligodendrocyte precursor cells (OPCs) into new myelinating oligodendrocytes may open new perspectives for ischaemic stroke treatment. In this respect, previous studies highlighted the role of the G protein-coupled membrane receptor 17 (GPR17) as a key regulator of OPC differentiation in experimental models of brain injury, including ischaemic stroke. To determine the translational value of GPR17 as a possible target in the context of human disease, we exploited immunohistochemistry to characterise the distribution of GPR17-expressing cells in brain tissue samples from ischaemic stroke cases and correlated it with the reactive state of neighbouring glial cells. The results showed that GPR17 specifically decorates a subpopulation of differentiation-committed OPCs, labelled by the peculiar marker breast carcinoma-amplified sequence 1 (BCAS1), that accumulates in the peri-infarct region in the later stages after the ischaemic event. Interestingly, the response of GPR17-expressing cells appears to be paralleled by the switch of reactive microglia/macrophages from a phagocytic to a dystrophic phenotype and by astrocytic scar formation. A negative correlation was found between GPR17-expressing OPCs and reactive microglia/macrophages and astrocytes surrounding chronic ischaemic lesions in female subjects, while the same relationship was less pronounced in males. These results were reinforced by bioinformatic analysis of a publicly available transcriptomic dataset, which implicated a possible role of inflammation and defective neuron-to-OPC communication in remyelination failure after ischaemic damage. Hence, these data strengthen the relevance of GPR17-based remyelinating therapies for the treatment of ischaemic stroke. © 2024 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":"226-243"},"PeriodicalIF":5.6,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862720","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":"Genomic characterization and histologic analysis of uterine leiomyosarcoma arising from leiomyoma with bizarre nuclei","authors":"Christopher Felicelli,&nbsp;Xinyan Lu,&nbsp;Zachary Coty-Fattal,&nbsp;Yue Feng,&nbsp;Ping Yin,&nbsp;Matthew John Schipma,&nbsp;Julie J Kim,&nbsp;Lawrence J Jennings,&nbsp;Serdar E Bulun,&nbsp;Jian-Jun Wei","doi":"10.1002/path.6379","DOIUrl":"10.1002/path.6379","url":null,"abstract":"<p>Leiomyoma with bizarre nuclei (LM-BN) is a rare variant of leiomyoma with a benign clinical course. In contrast, leiomyosarcoma (LMS) is a high-grade, malignant neoplasm characterized by high recurrence rates and poor survival. While LM-BN and LMS show distinct morphologies, they share similar immunoprofiles and molecular alterations, with both considered ‘genomically unstable’. Rare cases of LM-BN associated with LMS have been reported; however, the histogenesis and molecular relationship between these two tumors remains unclear. In this study, we assessed 11 cases of LMS arising in conjunction with LM-BN confirmed by histology and immunohistochemistry (IHC), further analyzed by clinical, histologic, and molecular characteristics of these distinct components. LM-BN and LMS had similar p16 and p53 IHC patterns, but LMS had a higher Ki-67 index and lower estrogen and progesterone eceptor expression. Digital image analysis based on cytologic features revealed spatial relationships between LMS and LM-BN. Genomic copy number alterations (CNAs) demonstrated the same clonal origin of LMS arising from existing LM-BN through conserved CNAs. LMS harbored highly complex CNAs and more frequent losses of the <i>TP53</i>, <i>RB1</i>, and <i>PTEN</i> genomic regions than LM-BN (<i>p</i> = 0.0031), with <i>CDKN2A/B</i> deletion identified in LMS only. Mutational profiling revealed many shared oncogenic alterations in both LM-BN and LMS; however, additional mutations were present within LMS, indicative of tumor progression through progressive genomic instability. Analysis of spatial transcriptomes defined uniquely expressed gene signatures that matched the geographic distribution of LM-BN, LMS, and other cell types. Our findings indicate for the first time that a subset of LMS arises from an existing LM-BN, and highly complex genomic alterations could be potential high risks associated with disease progression in LM-BN. © 2024 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":"211-225"},"PeriodicalIF":5.6,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845371","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":"Podocyte YAP ablation decreases podocyte adhesion and exacerbates FSGS progression through α3β1 integrin","authors":"Guangze Shao,&nbsp;Jitu Xu,&nbsp;Chencheng Hu,&nbsp;Wenyao Jia,&nbsp;Xitong Xu,&nbsp;Yue Gu,&nbsp;Luming Zhang,&nbsp;Zhihuang Zheng,&nbsp;Jiayan Zhong,&nbsp;Siqi Zhu,&nbsp;Shenghao Meng,&nbsp;Zhonghua Zhao,&nbsp;Zhigang Zhang,&nbsp;Jun Liu,&nbsp;Yanyong Xu,&nbsp;Huijuan Wu","doi":"10.1002/path.6370","DOIUrl":"10.1002/path.6370","url":null,"abstract":"<p>Severe proteinuria in focal segmental glomerulosclerosis (FSGS) is closely associated with decreased adhesion, and subsequent loss, of podocytes. Yes-associated protein (YAP) is a key transcriptional coactivator that plays a significant role in maintaining cellular homeostasis. However, its role in podocyte adhesion and its specific mechanism in FSGS progression remain unclear. In this study, an adriamycin (ADR)-induced FSGS model was established using podocyte-specific <i>Yap</i> knockout (KO) mice and control mice. These mice were further treated with Pyrintegrin, an agonist of α3β1 integrin, or a vehicle. Additionally, an ADR-induced FSGS model was constructed using podocyte-specific <i>Itga3</i> KO mice, which were subsequently treated with 1-oleoyl lysophosphatidic acid (LPA), a YAP activator, or a vehicle. Our findings demonstrated that YAP was positively correlated with podocyte adhesion. Podocyte-specific <i>Yap</i> KO mice exhibited reduced levels of α3β1 integrin and podocyte adhesion. <i>Yap</i> KO aggravated the ADR-induced reduction in α3β1 integrin and podocyte adhesion, resulting in significantly increased segmental or global glomerulosclerosis and proteinuria. Notably, treatment with a β1 integrin agonist partially ameliorated the decrease of podocyte adhesion and the worsening FSGS progression caused by <i>Yap</i> KO. Mechanistically, YAP was found to transcriptionally regulate α3- and β1 integrin via transcriptional enhanced associate domain 3 (TEAD3), with TEAD3 binding to the promoter region of <i>Itga3</i>. Furthermore, <i>Itga3</i> KO or knockdown abolished the beneficial effects of YAP activation on podocyte adhesion and FSGS progression. In conclusion, our results demonstrate that YAP regulates podocyte adhesion and FSGS progression through its transcriptional regulation of α3β1 integrin via TEAD3. This suggests that the YAP-TEAD3-α3β1 integrin axis may serve as a promising therapeutic target for FSGS. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 1","pages":"84-98"},"PeriodicalIF":5.6,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816795","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":"Stress testing deep learning models for prostate cancer detection on biopsies and surgical specimens","authors":"Brennan T Flannery,&nbsp;Howard M Sandler,&nbsp;Priti Lal,&nbsp;Michael D Feldman,&nbsp;Juan C Santa-Rosario,&nbsp;Tilak Pathak,&nbsp;Tuomas Mirtti,&nbsp;Xavier Farre,&nbsp;Rohann Correa,&nbsp;Susan Chafe,&nbsp;Amit Shah,&nbsp;Jason A Efstathiou,&nbsp;Karen Hoffman,&nbsp;Mark A Hallman,&nbsp;Michael Straza,&nbsp;Richard Jordan,&nbsp;Stephanie L Pugh,&nbsp;Felix Feng,&nbsp;Anant Madabhushi","doi":"10.1002/path.6373","DOIUrl":"10.1002/path.6373","url":null,"abstract":"<p>The presence, location, and extent of prostate cancer is assessed by pathologists using H&amp;E-stained tissue slides. Machine learning approaches can accomplish these tasks for both biopsies and radical prostatectomies. Deep learning approaches using convolutional neural networks (CNNs) have been shown to identify cancer in pathologic slides, some securing regulatory approval for clinical use. However, differences in sample processing can subtly alter the morphology between sample types, making it unclear whether deep learning algorithms will consistently work on both types of slide images. Our goal was to investigate whether morphological differences between sample types affected the performance of biopsy-trained cancer detection CNN models when applied to radical prostatectomies and vice versa using multiple cohorts (<i>N</i> = 1,000). Radical prostatectomies (<i>N</i> = 100) and biopsies (<i>N</i> = 50) were acquired from The University of Pennsylvania to train (80%) and validate (20%) a DenseNet CNN for biopsies (M^B), radical prostatectomies (M^R), and a combined dataset (M^B+R). On a tile level, M^B and M^R achieved F1 scores greater than 0.88 when applied to their own sample type but less than 0.65 when applied across sample types. On a whole-slide level, models achieved significantly better performance on their own sample type compared to the alternative model (<i>p</i> &lt; 0.05) for all metrics. This was confirmed by external validation using digitized biopsy slide images from a clinical trial [NRG Radiation Therapy Oncology Group (RTOG)] (NRG/RTOG 0521, <i>N</i> = 750) via both qualitative and quantitative analyses (<i>p</i> &lt; 0.05). A comprehensive review of model outputs revealed morphologically driven decision making that adversely affected model performance. M^B appeared to be challenged with the analysis of open gland structures, whereas M^R appeared to be challenged with closed gland structures, indicating potential morphological variation between the training sets. These findings suggest that differences in morphology and heterogeneity necessitate the need for more tailored, sample-specific (i.e. biopsy and surgical) machine learning models. © 2024 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":"146-157"},"PeriodicalIF":5.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805732","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}