The Journal of Pathology最新文献

{"title":"Nerve growth factor inducible (VGF) is a secreted mediator for metastatic breast cancer tropism to the brain","authors":"Rita Carvalho,&nbsp;Liliana Santos,&nbsp;Inês Conde,&nbsp;Ricardo Leitão,&nbsp;Hugo RS Ferreira,&nbsp;Célia Gomes,&nbsp;Ana Paula Silva,&nbsp;Fernando Schmitt,&nbsp;Carina Carvalho-Maia,&nbsp;João Lobo,&nbsp;Carmen Jerónimo,&nbsp;Joana Paredes,&nbsp;Ana Sofia Ribeiro","doi":"10.1002/path.6319","DOIUrl":"10.1002/path.6319","url":null,"abstract":"<p>Brain metastases are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we studied the impact of brain organotropic BC cells’ secretomes on the establishment of the brain pre-metastatic niche (PMN). We found that BC cells with specific tropism to the brain caused significant blood–brain barrier (BBB) disruption, as well as microglial activation, in both <i>in vitro</i> and <i>in vivo</i> models. Further, we searched for a brain-organotropic metastatic signature, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Of relevance, we identified VGF (nerve growth factor inducible) as a key mediator in this process, also impacting the BBB and microglial functions both <i>in vitro</i> and <i>in vivo</i>. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and the adjacent stroma. Importantly, VGF-positive tumors showed a significantly worse prognosis and were associated with HER2 (human epidermal growth factor receptor 2) overexpression and triple-negative molecular signatures. Further clinical validation in primary tumors from metastatic BC cases showed a significant association between VGF and the brain metastatic location, clearly and significantly impacting on the prognosis of BC patients with brain metastasis. In conclusion, our study reveals a unique secretome signature for BC with a tropism for the brain, highlighting VGF as a crucial mediator in this process. Furthermore, its specific impact as a poor prognostic predictor for BC patients with brain metastasis opens new avenues to target VGF to control the progression of brain metastatic disease. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 2","pages":"132-147"},"PeriodicalIF":5.6,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CCL2–CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop through glomerular macrophage and neutrophil infiltration in lupus nephritis","authors":"Takeshi Zoshima,&nbsp;Tomohisa Baba,&nbsp;Kimihiko Nakatani,&nbsp;Michio Nagata,&nbsp;Naofumi Mukaida,&nbsp;Mitsuhiro Kawano","doi":"10.1002/path.6331","DOIUrl":"10.1002/path.6331","url":null,"abstract":"<p>The CCL2–CCR2 axis is involved in lupus nephritis, however the precise roles in the mechanisms by which different pathological lesions develop after glomerular immune complex deposition remain elusive. Previously, we demonstrated that genetic CCR2 inhibition induced a histological switch from glomerular endocapillary hypercellularity to wire-loop lesions in murine lupus nephritis. This study aimed to clarify the CCL2–CCR2 axis-mediated cellular mechanism in the formation of these different pathological lesions. We injected MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 or B1, into wild-type (WT) mice to selectively induce glomerular endocapillary hypercellularity or wire-loop lesions. The expression of chemokine and chemokine receptors was analyzed using RT-quantitative PCR and/or immunofluorescence. We found 2B11.3 caused glomerular endocapillary hypercellularity in WT mice with glomerular infiltration of larger numbers of CCR2-expressing macrophages and neutrophils phagocyting immune complex, whereas B1 induced wire-loop lesions. In glomerular endocapillary hypercellularity, CCL2 was identified as the ligand involved in the CCR2-positive cell infiltration; it was expressed by glomerular endothelial cells and macrophages. Notably, 2B11.3-induced glomerular endocapillary hypercellularity converted to wire-loop lesions with reduced glomerular macrophage and neutrophil infiltration in CCL2-deficient (<i>Ccl2</i>^−/−) mice similarly observed in <i>C</i><i>cr2</i>^−/− mice. Moreover, this histological conversion was also observed when both glomerular macrophage and neutrophil infiltration were inhibited in anti-Ly6G antibody-treated <i>Ccr</i>5^−/− mice but not when only glomerular macrophage infiltration was inhibited in <i>Ccr5</i>^−/− mice or when only glomerular neutrophil infiltration was inhibited in anti-Ly6G antibody-treated WT mice. In contrast, B1 injection caused wire-loop lesions in <i>Ccl2</i>^−/− and <i>Ccr2</i>^−/− mice, as observed in WT mice. Moreover, 2B11.3 induced CCL2 from glomerular endothelial cells to a larger extent than B1 when injected into <i>Ccr2</i>^−/− mice. In conclusion, the CCL2–CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop by regulating glomerular infiltration of phagocytic cells: macrophages and neutrophils. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 2","pages":"174-185"},"PeriodicalIF":5.6,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756026","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":"Analyses of combined Merkel cell carcinomas with neuroblastic components suggests that loss of T antigen expression in Merkel cell carcinoma may result in cell cycle arrest and neuroblastic transdifferentiation","authors":"Thibault Kervarrec,&nbsp;Silke Appenzeller,&nbsp;Susanne Gramlich,&nbsp;Etienne Coyaud,&nbsp;Kamel Bachiri,&nbsp;Romain Appay,&nbsp;Nicolas Macagno,&nbsp;Anne Tallet,&nbsp;Christine Bonenfant,&nbsp;Yannick Lecorre,&nbsp;Jean Kapfer,&nbsp;Sami Kettani,&nbsp;Nalini Srinivas,&nbsp;Kuan Cheok Lei,&nbsp;Anja Lange,&nbsp;Jürgen C Becker,&nbsp;Eva Maria Sarosi,&nbsp;Hervé Sartelet,&nbsp;Andreas von Deimling,&nbsp;Antoine Touzé,&nbsp;Serge Guyétant,&nbsp;Mahtab Samimi,&nbsp;David Schrama,&nbsp;Roland Houben","doi":"10.1002/path.6304","DOIUrl":"10.1002/path.6304","url":null,"abstract":"<p>Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by genomic integration of the Merkel cell polyomavirus (MCPyV). MCPyV-negative cases often present as combined MCCs, which represent a distinctive subset of tumors characterized by association of an MCC with a second tumor component, mostly squamous cell carcinoma. Up to now, only exceptional cases of combined MCC with neuroblastic differentiation have been reported. Herein we describe two additional combined MCCs with neuroblastic differentiation and provide comprehensive morphologic, immunohistochemical, transcriptomic, genetic and epigenetic characterization of these tumors, which both arose in elderly men and appeared as an isolated inguinal adenopathy. Microscopic examination revealed biphasic tumors combining a poorly differentiated high-grade carcinoma with a poorly differentiated neuroblastic component lacking signs of proliferation. Immunohistochemical investigation revealed keratin 20 and MCPyV T antigen (TA) in the MCC parts, while neuroblastic differentiation was confirmed in the other component in both cases. A clonal relation of the two components can be deduced from 20 and 14 shared acquired point mutations detected by whole exome analysis in both combined tumors, respectively. Spatial transcriptomics demonstrated a lower expression of stem cell marker genes such as <i>SOX2</i> and <i>MCM2</i> in the neuroblastic component. Interestingly, although the neuroblastic part lacked TA expression, the same genomic MCPyV integration and the same large T-truncating mutations were observed in both tumor parts. Given that neuronal transdifferentiation upon TA repression has been reported for MCC cell lines, the most likely scenario for the two combined MCC/neuroblastic tumors is that neuroblastic transdifferentiation resulted from loss of TA expression in a subset of MCC cells. Indeed, DNA methylation profiling suggests an MCC-typical cellular origin for the combined MCC/neuroblastomas. © 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":"264 1","pages":"112-124"},"PeriodicalIF":5.6,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6304","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756025","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":"TP53 mutations in urothelial carcinoma: not all one and the same†","authors":"Alexis R Barr,&nbsp;Amy Burley,&nbsp;Anna Wilkins","doi":"10.1002/path.6335","DOIUrl":"10.1002/path.6335","url":null,"abstract":"<p>Systemic therapy options for urothelial carcinoma have expanded in recent years, with both immunotherapy and cytotoxic chemotherapy being widely available. However, we lack biomarkers to select which drug is likely to work best in individual patients. A new article in this journal by Jin, Xu, Su, <i>et al</i> reports that disruptive versus non-disruptive <i>TP53</i> mutations may guide these personalised therapy choices. Intriguingly, patients with disruptive <i>TP53</i> tumour mutations had poor overall survival versus those with non-disruptive <i>TP53</i> mutations or wild type <i>TP53</i> but responded particularly well to immunotherapy. Of relevance, an increased tumour mutational burden and increased effector CD8⁺ T-cell infiltration was seen in tumours with disruptive mutations. The impact of different <i>TP53</i> mutations on prognosis and therapy choices appears to be tumour- and therapy-type specific, with no clear consensus on overall tumour phenotype according to type of mutation. Nonetheless, profiling of specific types of <i>TP53</i> mutation is increasingly clinically feasible with targeted sequencing or immunohistochemistry. There is an urgent need for additional studies in urothelial cancer clarifying how the type of <i>TP53</i> mutation present within a tumour can best be used as a predictive biomarker. Further important remaining questions include the impact of <i>TP53</i> mutations on other clinically important aspects of the tumour microenvironment, including cancer-associated fibroblasts. Furthermore, the impact of gain-of-function mutations in <i>TP53</i> and other related genes signalling upstream or downstream of <i>TP53</i> is of wide interest. © 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":"264 2","pages":"125-128"},"PeriodicalIF":5.6,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6335","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750718","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":"Histone demethylase PHF8 promotes prostate cancer metastasis via the E2F1–SNAI1 axis","authors":"Ze Wang,&nbsp;Peng Tang,&nbsp;Haiyang Xiao,&nbsp;Song Peng,&nbsp;Jian Chen,&nbsp;Yapeng Wang,&nbsp;Jing Xu,&nbsp;Qian Yan,&nbsp;Junying Zhang,&nbsp;Jie Deng,&nbsp;Qiang Ma,&nbsp;Hailin Zhu,&nbsp;Weiming Luo,&nbsp;Dianzheng Zhang,&nbsp;Luofu Wang,&nbsp;Jun Qin,&nbsp;Weihua Lan,&nbsp;Jun Jiang,&nbsp;Qiuli Liu","doi":"10.1002/path.6325","DOIUrl":"10.1002/path.6325","url":null,"abstract":"<p>Metastasis is the primary culprit behind cancer-related fatalities in multiple cancer types, including prostate cancer. Despite great advances, the precise mechanisms underlying prostate cancer metastasis are far from complete. By using a transgenic mouse prostate cancer model (TRAMP) with and without <i>Phf8</i> knockout, we have identified a crucial role of PHF8 in prostate cancer metastasis. By complexing with E2F1, PHF8 transcriptionally upregulates SNAI1 in a demethylation-dependent manner. The upregulated SNAI1 subsequently enhances epithelial-to-mesenchymal transition (EMT) and metastasis. Given the role of the abnormally activated PHF8/E2F1-SNAI1 axis in prostate cancer metastasis and poor prognosis, the levels of PHF8 or the activity of this axis could serve as biomarkers for prostate cancer metastasis. Moreover, targeting this axis could become a potential therapeutic strategy for prostate cancer treatment. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 1","pages":"68-79"},"PeriodicalIF":5.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632173","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":"Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease","authors":"María Ángeles Núñez-Sánchez,&nbsp;María Antonia Martínez-Sánchez,&nbsp;Marta Sierra-Cruz,&nbsp;Ana Lambertos,&nbsp;Sara Rico-Chazarra,&nbsp;Alba Oliva-Bolarín,&nbsp;Andrés Balaguer-Román,&nbsp;José Enrique Yuste,&nbsp;Carlos Manuel Martínez,&nbsp;Adriana Mika,&nbsp;María Dolores Frutos,&nbsp;Camilo J Llamoza-Torres,&nbsp;José Córdoba-Chacón,&nbsp;Bruno Ramos-Molina","doi":"10.1002/path.6330","DOIUrl":"10.1002/path.6330","url":null,"abstract":"<p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate-limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet-induced MASH mice and patients with biopsy-proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in <i>in vitro</i> assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK-18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 1","pages":"101-111"},"PeriodicalIF":5.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632174","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":"Functional ex vivo DNA fibre assay to measure replication dynamics in breast cancer tissue","authors":"Mengting Chen,&nbsp;Nathalie van den Tempel,&nbsp;Arkajyoti Bhattacharya,&nbsp;Shibo Yu,&nbsp;Bea Rutgers,&nbsp;Rudolf SN Fehrmann,&nbsp;Sander de Haas,&nbsp;Bert van der Vegt,&nbsp;Marcel ATM van Vugt","doi":"10.1002/path.6328","DOIUrl":"10.1002/path.6328","url":null,"abstract":"<p>Replication stress (RS) is a key trait of cancer cells, and a potential actionable target in cancer treatment. Accurate methods to measure RS in tumour samples are currently lacking. DNA fibre analysis has been used as a common technique to measure RS in cell lines. Here, we investigated DNA fibre analysis on fresh breast cancer specimens and correlated DNA replication kinetics to known RS markers and genomic alterations. Fresh, treatment-naïve primary breast cancer samples (<i>n</i> = 74) were subjected to <i>ex vivo</i> DNA fibre analysis to measure DNA replication kinetics. Tumour cell proliferation was confirmed by EdU incorporation and cytokeratin AE1/AE3 (CK) staining. The RS markers phospho-S33-RPA and γH2AX and the RS-inducing proto-oncogenes Cyclin E1 and c-Myc were analysed by immunohistochemistry. Copy number variations (CNVs) were assessed from genome-wide single nucleotide polymorphism (SNP) arrays. We found that the majority of proliferating (EdU-positive) cells in each sample were CK-positive and therefore considered to be tumour cells. DNA fibre lengths varied largely in most tumour samples. The median DNA fibre length showed a significant inverse correlation with pRPA expression (<i>r</i> = −0.29, <i>p</i> = 0.033) but was not correlated with Cyclin E1 or c-Myc expression and global CNVs in this study. Nuclear Cyclin E1 expression showed a positive correlation with pRPA levels (<i>r</i> = 0.481, <i>p</i> &lt; 0.0001), while cytoplasmic Cyclin E1 expression exhibited an inverse association with pRPA expression (<i>r</i> = −0.353, <i>p</i> = 0.002) and a positive association with global CNVs (<i>r</i> = 0.318, <i>p</i> = 0.016). In conclusion, DNA fibre analysis performed with fresh primary breast cancer samples is feasible. Fibre lengths were associated with pRPA expression. Cyclin E1 expression was associated with pRPA and the percentage of CNVs. © 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":"264 1","pages":"90-100"},"PeriodicalIF":5.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6328","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632172","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":"Multiregion exome sequencing indicates a monoclonal origin of esophageal spindle-cell squamous cell carcinoma","authors":"Yulu Wang,&nbsp;Qian Zhu,&nbsp;Yaqing Wu,&nbsp;Boyi Li,&nbsp;Xiaoxing Su,&nbsp;Chan Xiang,&nbsp;Yuchen Han","doi":"10.1002/path.6324","DOIUrl":"10.1002/path.6324","url":null,"abstract":"<p>Esophageal spindle-cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of a carcinomatous component (CaC) and a sarcomatous component (SaC). However, the genomic origin and gene signature of ESS remain unclear. Using whole-exome sequencing of laser-capture microdissection (LCM) tumor samples, we determined that CaC and SaC showed high mutational commonality, with the same top high-frequency mutant genes, mutation signatures, and tumor mutation burden; paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK–RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was <i>TP53</i>, followed by <i>NFE2L2</i>, <i>KMT2D</i>, and <i>MUC16</i>. Prognostic associations were found for <i>CDC27</i>, <i>LRP2</i>, <i>APC</i>, and <i>SNAPC4</i>. Our data highlight the monoclonal origin of ESS with <i>TP53</i> as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 1","pages":"55-67"},"PeriodicalIF":5.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632175","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":"Disorganisation of basement membrane zone architecture impairs melanocyte residence in vitiligo","authors":"Fei Yang,&nbsp;Lingli Yang,&nbsp;Yasutaka Kuroda,&nbsp;Sylvia Lai,&nbsp;Yoshito Takahashi,&nbsp;Tetsuya Sayo,&nbsp;Takeshi Namiki,&nbsp;Kimiko Nakajima,&nbsp;Shigetoshi Sano,&nbsp;Shintaro Inoue,&nbsp;Daisuke Tsuruta,&nbsp;Ichiro Katayama","doi":"10.1002/path.6321","DOIUrl":"10.1002/path.6321","url":null,"abstract":"<p>The basement membrane zone is the interface between the epidermis and dermis, and it is disrupted in several skin conditions. Here, we report the results of a comprehensive investigation into the structural and molecular factors of the basement membrane zone in vitiligo, a dermatological disorder characterised by depigmented patches on the skin. Using electron microscopy and immunofluorescence staining, we confirmed abnormal basement membrane zone morphology and disrupted basement membrane zone architecture in human vitiliginous skin. Furthermore, we identified elevated expression of matrix metalloproteinase 2 (MMP2) in human dermal fibroblasts as a key factor responsible for basement membrane zone matrix degradation. In our <i>in vitro</i> and <i>ex vivo</i> models, overexpression of MMP2 in fibroblasts led to basement membrane zone disruption and melanocyte disappearance. Importantly, we reveal that the loss of melanocytes in vitiligo is primarily linked to their weakened adhesion to the basement membrane, mediated by binding between integrin β1 and laminin and discoidin domain receptor 1 and collagen IV. Finally, inhibition of matrix metalloproteinase 2 expression reversed depigmentation in a mouse model of vitiligo. In conclusion, our research shows the importance of basement membrane zone integrity in melanocyte residence and offers new avenues for therapeutic interventions to address this challenging skin condition. © 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":"264 1","pages":"30-41"},"PeriodicalIF":5.6,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578490","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":"Development of a multi-scanner facility for data acquisition for digital pathology artificial intelligence","authors":"Matthew P Humphries,&nbsp;Danny Kaye,&nbsp;Gaby Stankeviciute,&nbsp;Jacob Halliwell,&nbsp;Alexander I Wright,&nbsp;Daljeet Bansal,&nbsp;David Brettle,&nbsp;Darren Treanor","doi":"10.1002/path.6326","DOIUrl":"10.1002/path.6326","url":null,"abstract":"<p>Whole slide imaging (WSI) of pathology glass slides using high-resolution scanners has enabled the large-scale application of artificial intelligence (AI) in pathology, to support the detection and diagnosis of disease, potentially increasing efficiency and accuracy in tissue diagnosis. Despite the promise of AI, it has limitations. ‘Brittleness’ or sensitivity to variation in inputs necessitates that large amounts of data are used for training. AI is often trained on data from different scanners but not usually by replicating the same slide across scanners. The utilisation of multiple WSI instruments to produce digital replicas of the same slides will make more comprehensive datasets and may improve the robustness and generalisability of AI algorithms as well as reduce the overall data requirements of AI training. To this end, the National Pathology Imaging Cooperative (NPIC) has built the AI FORGE (Facilitating Opportunities for Robust Generalisable data Emulation), a unique multi-scanner facility embedded in a clinical site in the NHS to (1) compare scanner performance, (2) replicate digital pathology image datasets across WSI systems, and (3) support the evaluation of clinical AI algorithms. The NPIC AI FORGE currently comprises 15 scanners from nine manufacturers. It can generate approximately 4,000 WSI images per day (approximately 7 TB of image data). This paper describes the process followed to plan and build such a facility. © 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":"264 1","pages":"80-89"},"PeriodicalIF":5.6,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6326","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562163","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}