The Journal of Pathology最新文献

{"title":"Genetic and epigenetic alterations in precursor lesions of endometrial endometrioid carcinoma","authors":"Osamu Gotoh,&nbsp;Yuko Sugiyama,&nbsp;Akiko Tonooka,&nbsp;Mayuko Kosugi,&nbsp;Sunao Kitaura,&nbsp;Ryu Minegishi,&nbsp;Masatoshi Sano,&nbsp;Sayuri Amino,&nbsp;Rie Furuya,&nbsp;Norio Tanaka,&nbsp;Tomoko Kaneyasu,&nbsp;Kohei Kumegawa,&nbsp;Akiko Abe,&nbsp;Hidetaka Nomura,&nbsp;Yutaka Takazawa,&nbsp;Hiroyuki Kanao,&nbsp;Reo Maruyama,&nbsp;Tetsuo Noda,&nbsp;Seiichi Mori","doi":"10.1002/path.6278","DOIUrl":"10.1002/path.6278","url":null,"abstract":"<p>The hyperplasia–carcinoma sequence is a stepwise tumourigenic programme towards endometrial cancer in which normal endometrial epithelium becomes neoplastic through non-atypical endometrial hyperplasia (NAEH) and atypical endometrial hyperplasia (AEH), under the influence of unopposed oestrogen. NAEH and AEH are known to exhibit polyclonal and monoclonal cell growth, respectively; yet, aside from focal PTEN protein loss, the genetic and epigenetic alterations that occur during the cellular transition remain largely unknown. We sought to explore the potential molecular mechanisms that promote the NAEH–AEH transition and identify molecular markers that could help to differentiate between these two states. We conducted target-panel sequencing on the coding exons of 596 genes, including 96 endometrial cancer driver genes, and DNA methylome microarrays for 48 NAEH and 44 AEH lesions that were separately collected via macro- or micro-dissection from the endometrial tissues of 30 cases. Sequencing analyses revealed acquisition of the <i>PTEN</i> mutation and the clonal expansion of tumour cells in AEH samples. Further, across the transition, alterations to the DNA methylome were characterised by hypermethylation of promoter/enhancer regions and CpG islands, as well as hypo- and hyper-methylation of DNA-binding regions for transcription factors relevant to endometrial cell differentiation and/or tumourigenesis, including FOXA2, SOX17, and HAND2. The identified DNA methylation signature distinguishing NAEH and AEH lesions was reproducible in a validation cohort with modest discriminative capability. These findings not only support the concept that the transition from NAEH to AEH is an essential step within neoplastic cell transformation of endometrial epithelium but also provide deep insight into the molecular mechanism of the tumourigenic programme. © 2024 The Authors. <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":"263 3","pages":"275-287"},"PeriodicalIF":7.3,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6278","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140907690","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":"Megalin-related mechanism of hemolysis-induced acute kidney injury and the therapeutic strategy","authors":"Sawako Goto,&nbsp;Michihiro Hosojima,&nbsp;Hideyuki Kabasawa,&nbsp;Kaho Arai,&nbsp;Kazuya Takemoto,&nbsp;Hiroyuki Aoki,&nbsp;Koichi Komochi,&nbsp;Ryota Kobayashi,&nbsp;Nanako Sugita,&nbsp;Taeko Endo,&nbsp;Ryohei Kaseda,&nbsp;Yutaka Yoshida,&nbsp;Ichiei Narita,&nbsp;Yoshiaki Hirayama,&nbsp;Akihiko Saito","doi":"10.1002/path.6284","DOIUrl":"10.1002/path.6284","url":null,"abstract":"<p>Hemolysis-induced acute kidney injury (AKI) is attributed to heme-mediated proximal tubule epithelial cell (PTEC) injury and tubular cast formation due to intratubular protein condensation. Megalin is a multiligand endocytic receptor for proteins, peptides, and drugs in PTECs and mediates the uptake of free hemoglobin and the heme-scavenging protein α₁-microglobulin. However, understanding of how megalin is involved in the development of hemolysis-induced AKI remains elusive. Here, we investigated the megalin-related pathogenesis of hemolysis-induced AKI and a therapeutic strategy using cilastatin, a megalin blocker. A phenylhydrazine-induced hemolysis model developed in kidney-specific mosaic megalin knockout (MegKO) mice confirmed megalin-dependent PTEC injury revealed by the co-expression of kidney injury molecule-1 (KIM-1). In the hemolysis model in kidney-specific conditional MegKO mice, the uptake of hemoglobin and α₁-microglobulin as well as KIM-1 expression in PTECs was suppressed, but tubular cast formation was augmented, likely due to the nonselective inhibition of protein reabsorption in PTECs. Quartz crystal microbalance analysis revealed that cilastatin suppressed the binding of megalin with hemoglobin and α₁-microglobulin. Cilastatin also inhibited the specific uptake of fluorescent hemoglobin by megalin-expressing rat yolk sac tumor-derived L2 cells. In a mouse model of hemolysis-induced AKI, repeated cilastatin administration suppressed PTEC injury by inhibiting the uptake of hemoglobin and α₁-microglobulin and also prevented cast formation. Hemopexin, another heme-scavenging protein, was also found to be a novel ligand of megalin, and its binding to megalin and uptake by PTECs in the hemolysis model were suppressed by cilastatin. Mass spectrometry-based semiquantitative analysis of urinary proteins in cilastatin-treated C57BL/6J mice indicated that cilastatin suppressed the reabsorption of a limited number of megalin ligands in PTECs, including α₁-microglobulin and hemopexin. Collectively, cilastatin-mediated selective megalin blockade is an effective therapeutic strategy to prevent both heme-mediated PTEC injury and cast formation in hemolysis-induced AKI. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 3","pages":"315-327"},"PeriodicalIF":7.3,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896619","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":"Multiomics sequencing and immune microenvironment characteristics define three subtypes of small cell neuroendocrine carcinoma of the cervix","authors":"Baoyue Pan,&nbsp;Shumei Yan,&nbsp;Linjing Yuan,&nbsp;Huiling Xiang,&nbsp;Mingxiu Ju,&nbsp;Shijie Xu,&nbsp;Weihua Jia,&nbsp;Jundong Li,&nbsp;Qi Zhao,&nbsp;Min Zheng","doi":"10.1002/path.6290","DOIUrl":"10.1002/path.6290","url":null,"abstract":"<p>Small cell cervical carcinoma (SCCC) is the most common neuroendocrine tumor in the female genital tract, with an unfavorable prognosis and lacking an evidence-based therapeutic approach. Until now, the distinct subtypes and immune characteristics of SCCC combined with genome and transcriptome have not been described. We performed genomic (<i>n</i> = 18), HPV integration (<i>n</i> = 18), and transcriptomic sequencing (<i>n</i> = 19) of SCCC samples. We assessed differences in immune characteristics between SCCC and conventional cervical cancer, and other small cell neuroendocrine carcinomas, through bioinformatics analysis and immunohistochemical assays. We stratified SCCC patients through non-negative matrix factorization and described the characteristics of these distinct types. We further validated it using multiplex immunofluorescence (<i>n</i> = 77) and investigated its clinical prognostic effect. We confirmed a high frequency of <i>PIK3CA</i> and <i>TP53</i> alterations and HPV18 integrations in SCCC. SCCC and other small cell carcinoma had similar expression signatures and immune cell infiltration patterns. Comparing patients with SCCC to those with conventional cervical cancer, the former presented immune excluded or ‘desert’ infiltration. The number of CD8+ cells in the invasion margin of SCCC patients predicted favorable clinical outcomes. We identified three transcriptome subtypes: an inflamed phenotype with high-level expression of genes related to the MHC-II complex (<i>CD74</i>) and IFN-α/β (SCCC-I), and two neuroendocrine subtypes with high-level expression of <i>ASCL1</i> or <i>NEUROD1</i>, respectively. Combined with multiple technologies, we found that the neuroendocrine groups had more <i>TP53</i> mutations and SCCC-I had more <i>PIK3CA</i> mutations. Multiplex immunofluorescence validated these subtypes and SCCC-I was an independent prognostic factor of overall survival. These results provide insights into SCCC tumor heterogeneity and potential therapies. © 2024 The Authors. <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":"263 3","pages":"372-385"},"PeriodicalIF":7.3,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6290","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896623","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":"RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma-like mesenchymal tumors","authors":"Marialetizia Motta,&nbsp;Sabina Barresi,&nbsp;Simone Pizzi,&nbsp;Delfina Bifano,&nbsp;Jennifer Lopez Marti,&nbsp;Marta Garrido-Pontnou,&nbsp;Elisabetta Flex,&nbsp;Alessandro Bruselles,&nbsp;Isabella Giovannoni,&nbsp;Giovannina Rotundo,&nbsp;Alessandra Fragale,&nbsp;Valentina Tirelli,&nbsp;Silvia Vallese,&nbsp;Andrea Ciolfi,&nbsp;Gianni Bisogno,&nbsp;Rita Alaggio,&nbsp;Marco Tartaglia","doi":"10.1002/path.6272","DOIUrl":"10.1002/path.6272","url":null,"abstract":"<p>Infantile fibrosarcomas (IFS) and congenital mesoblastic nephroma (CMN) are rare myofibroblastic tumors of infancy and early childhood commonly harboring the <i>ETV6</i>::<i>NTRK3</i> gene fusion. IFS/CMN are considered as tumors with an ‘intermediate prognosis’ as they are locally aggressive, but rarely metastasize, and generally have a favorable outcome. A fraction of IFS/CMN-related neoplasms are negative for the <i>ETV6</i>::<i>NTRK3</i> gene rearrangement and are characterized by other chimeric proteins promoting MAPK signaling upregulation. In a large proportion of these tumors, which are classified as IFS-like mesenchymal neoplasms, the contributing molecular events remain to be identified. Here, we report three distinct rearrangements involving <i>RAF1</i> among eight <i>ETV6</i>::<i>NTRK3</i> gene fusion-negative tumors with an original histological diagnosis of IFS/CMN. The three fusion proteins retain the entire catalytic domain of the kinase. Two chimeric products, GOLGA4::RAF1 and LRRFIP2::RAF1, had previously been reported as driver events in different cancers, whereas the third, CLIP1::RAF1, represents a novel fusion protein. We demonstrate that CLIP1::RAF1 acts as a <i>bona fide</i> oncoprotein promoting cell proliferation and migration through constitutive upregulation of MAPK signaling. We show that the CLIP1::RAF1 hyperactive behavior does not require RAS activation and is mediated by constitutive 14-3-3 protein-independent dimerization of the chimeric protein. As previously reported for the ETV6::NTRK3 fusion protein, CLIP1::RAF1 similarly upregulates PI3K-AKT signaling. Our findings document that <i>RAF1</i> gene rearrangements represent a recurrent event in <i>ETV6</i>::<i>NTRK3</i>-negative IFS/CMN and provide a rationale for the use of inhibitors directed to suppress MAPK and PI3K-AKT signaling in these cancers. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 2","pages":"166-177"},"PeriodicalIF":7.3,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140609233","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":"ΔNp73 and its effector targets promote colorectal peritoneal carcinosis and predict survival","authors":"Daniel Pastor-Morate,&nbsp;Lidia Amigo-Morán,&nbsp;María Garranzo-Asensio,&nbsp;Raquel Rejas-González,&nbsp;Patricia Carnicero,&nbsp;Nuria Rodríguez,&nbsp;Juan Pedro Pérez-Robledo,&nbsp;Rodrigo Barderas,&nbsp;Isabel Prieto-Nieto,&nbsp;Gemma Domínguez","doi":"10.1002/path.6286","DOIUrl":"10.1002/path.6286","url":null,"abstract":"<p>Peritoneal metastasis of colorectal origin appears in ~10–15% of patients at the time of diagnosis and in 30–40% of cases with disease progression. Locoregional spread through the peritoneum is considered stage IVc and is associated with a poor prognosis. The development of a regional therapeutic strategy based on cytoreductive surgery, and hyperthermic intra-abdominal chemotherapy has significantly altered the course of the disease. Although recent evidence supports the benefits of cytoreductive surgery, the benefits of hyperthermic intra-abdominal chemotherapy are, however, still a matter of debate. Understanding the molecular alterations underlying the disease is crucial for developing new therapeutic strategies. Here, we evaluated the involvement in peritoneal dissemination of the oncogenic isoform of <i>TP73</i>, <i>ΔNp73</i>, and its effector targets in <i>in vitro</i> and mouse models, and in 30 patients diagnosed with colorectal peritoneal metastasis. In an orthotopic mouse model, we observed that tumor cells overexpressing <i>ΔNp73</i> present a higher avidity for the peritoneum and that extracellular vesicles secreted by <i>ΔNp73</i>-upregulating tumor cells enhance their dissemination. In addition, we identified that tumor cells overexpressing <i>ΔNp73</i> present with dysregulation of genes associated with an epithelial/mesothelial-to-mesenchymal transition (MMT) and that mesothelial cells exposed to the conditioned medium of tumor cells with upregulated <i>ΔNp73</i> present a mesenchymal phenotype. Lastly, <i>ΔNp73</i> and its effector target RNAs were dysregulated in our patient series, there were positive correlations between <i>ΔNp73</i> and its effector targets, and <i>MSN</i> and <i>ITGB4</i> (<i>ΔNp73</i> effectors) predicted patient survival. In conclusion, <i>ΔNp73</i> and its effector targets are involved in the peritoneal dissemination of colorectal cancer and predict patient survival. The promotion of the EMT/MMT and modulation of the adhesion capacity in colorectal cancer cells might be the mechanisms triggered by <i>ΔNp73</i>. Remarkably, ΔNp73 protein is a druggable protein and should be the focus of future studies. © 2024 The Authors. <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":"263 3","pages":"328-337"},"PeriodicalIF":7.3,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6286","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140617586","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":"Acquired NF2 mutation confers resistance to TRK inhibition in an ex vivo LMNA::NTRK1-rearranged soft-tissue sarcoma cell model","authors":"Yanjiang Chen,&nbsp;Sabrina Steiner,&nbsp;Catherine Hagedorn,&nbsp;Sarah Kollar,&nbsp;Alicia Pliego-Mendieta,&nbsp;Martina Haberecker,&nbsp;Jan Plock,&nbsp;Christian Britschgi,&nbsp;Lara Planas-Paz,&nbsp;Chantal Pauli","doi":"10.1002/path.6282","DOIUrl":"10.1002/path.6282","url":null,"abstract":"<p>Genomic rearrangements of the neurotrophic receptor tyrosine kinase genes (<i>NTRK1, NTRK2</i>, and <i>NTRK3</i>) are the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation. Several targeted therapies have been approved for tumours harbouring <i>NTRK</i> fusions and a new generation of TRK inhibitors has already been developed due to acquired resistance. We established a patient-derived <i>LMNA</i>::<i>NTRK1</i>-rearranged soft-tissue sarcoma cell model <i>ex vivo</i> with an acquired resistance to targeted TRK inhibition. Molecular profiling of the resistant clones revealed an acquired <i>NF2</i> loss of function mutation that was absent in the parental cell model. Parental cells showed continuous sensitivity to TRK-targeted treatment, whereas the resistant clones were insensitive. Furthermore, resistant clones showed upregulation of the MAPK and mTOR/AKT pathways in the gene expression based on RNA sequencing data and increased sensitivity to MEK and mTOR inhibitor therapy. Drug synergy was seen using trametinib and rapamycin in combination with entrectinib. Medium-throughput drug screening further identified small compounds as potential drug candidates to overcome resistance as monotherapy or in combination with entrectinib. In summary, we developed a comprehensive model of drug resistance in an <i>LMNA</i>::<i>NTRK1</i>-rearranged soft-tissue sarcoma and have broadened the understanding of acquired drug resistance to targeted TRK therapy. Furthermore, we identified drug combinations and small compounds to overcome acquired drug resistance and potentially guide patient care in a functional precision oncology setting. © 2024 The Authors. <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":"263 2","pages":"257-269"},"PeriodicalIF":7.3,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6282","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593162","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":"Enhanced prostatic Esr1+ luminal epithelial cells in the absence of SRD5A2","authors":"Christina Sharkey,&nbsp;Xingbo Long,&nbsp;Ra'ad Al-Faouri,&nbsp;Douglas Strand,&nbsp;Aria F Olumi,&nbsp;Zongwei Wang","doi":"10.1002/path.6283","DOIUrl":"10.1002/path.6283","url":null,"abstract":"<p>Steroid 5α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and is crucial for prostatic development. 5α reductase inhibitors (5ARI) reduce prostate size in benign prostate hyperplasia (BPH) and ameliorate lower urinary tract symptoms secondary to BPH. However, the mechanisms of 5ARI functioning are still not fully understood. Here, we used a <i>Srd5a2</i>^−/− mouse model and employed single-cell RNA sequencing to explore the impact of SRD5A2 absence on prostate cellular heterogeneity. Significant alterations in luminal epithelial cell (LE) populations were observed, alongside an increased proportion and proliferative phenotype of estrogen receptor 1 (ESR1)⁺ LE2 cells, following an SRD5A2-independent ESR1 differentiation trajectory. LE2 cells exhibited enhanced estrogen response gene signatures, suggesting an alternative pathway for prostate growth when SRD5A2 is absent. Human prostate biopsy analysis revealed an inverse correlation between the expressions of SRD5A2 and LE2 markers (ESR1/PKCα), and an inverse correlation between SRD5A2 and the clinical efficiency of 5ARI. These findings provide insights into 5ARI resistance mechanisms and potential alternative therapies for BPH-related lower urinary tract symptoms. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 3","pages":"300-314"},"PeriodicalIF":7.3,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593523","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":"From morphology to methylome: epigenetic studies of Müllerian mesonephric-like adenocarcinoma reveal similarities to cervical mesonephric adenocarcinoma†","authors":"Lawrence H Lin,&nbsp;Brooke E Howitt,&nbsp;David L Kolin","doi":"10.1002/path.6285","DOIUrl":"10.1002/path.6285","url":null,"abstract":"<p>Mesonephric adenocarcinomas (MAs) and mesonephric-like adenocarcinomas (MLAs) are rare, aggressive neoplasms that arise in the gynecologic tract and show overlapping morphologic, immunohistochemical, and molecular features. While MAs occur in the cervix and are thought to arise from mesonephric remnants, MLAs occur in the endometrium and ovary and are believed to originate from transdifferentiation of Müllerian lesions. Both MAs and MLAs show a variety of architectural patterns, exhibit frequent expression of GATA3 by immunohistochemistry, and harbor <i>KRAS</i> mutations. In a recent article published in <i>The Journal of Pathology</i>, Kommoss and colleagues used DNA methylation profiling to extend these similarities and showed that MLAs and MAs cluster together based on their epigenetic signatures and are epigenetically distinct from other Müllerian adenocarcinomas. They also showed that MLAs and MAs harbor a high number of global copy number alterations. This study provides evidence that MLAs more closely resemble MAs than Müllerian carcinomas on an epigenetic level. As a result, the authors argue that MLA should be renamed ‘mesonephric-type adenocarcinoma.’ Further research is needed to establish the relationship between these two entities, their etiology, and pathogenesis. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 2","pages":"135-138"},"PeriodicalIF":7.3,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6285","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593001","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":"TGF-β3 from fibroblasts promotes necrotising sialometaplasia by suppressing salivary gland cell proliferation and inducing squamous metaplasia","authors":"Shohei Yoshimoto,&nbsp;Naomi Yada,&nbsp;Ayataka Ishikawa,&nbsp;Kenji Kawano,&nbsp;Kou Matsuo,&nbsp;Akimitsu Hiraki,&nbsp;Kazuhiko Okamura","doi":"10.1002/path.6287","DOIUrl":"10.1002/path.6287","url":null,"abstract":"<p>Necrotising sialometaplasia (NSM) is a non-neoplastic lesion mainly arising in the minor salivary glands of the oral cavity. In the clinical features, NSM shows swelling with or without ulceration, and can mimic a malignant disease such as squamous cell carcinoma. Histopathologically, NSM usually shows the lobular architecture that is observed in the salivary glands. Additionally, acinar infarction and squamous metaplasia of salivary ducts and acini are observable. The aetiology of this lesion remains unknown, although it has a characteristic feature that sometimes requires clinical and histopathological differentiation from malignancy. In this study, we investigated upregulated genes in NSM compared with normal salivary glands, and focused on the TGF-β3 (<i>TGFB3</i>) gene. The results of the histopathological studies clarified that fibroblasts surrounding the lesion express TGF-β3. Moreover, <i>in vitro</i> studies using mouse salivary gland organoids revealed that TGF-β3 suppressed salivary gland cell proliferation and induced squamous metaplasia. We demonstrated a possible aetiology of NSM by concluding that increased TGF-β3 expression during wound healing or tissue regeneration played a critical role in cell proliferation and metaplasia. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 3","pages":"338-346"},"PeriodicalIF":7.3,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140602999","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":"Co-targeting BET, CBP, and p300 inhibits neuroendocrine signalling in androgen receptor-null prostate cancer","authors":"Nicholas Choo,&nbsp;Shivakumar Keerthikumar,&nbsp;Susanne Ramm,&nbsp;Daisaku Ashikari,&nbsp;Linda Teng,&nbsp;Birunthi Niranjan,&nbsp;Shelley Hedwards,&nbsp;Laura H Porter,&nbsp;David L Goode,&nbsp;Kaylene J Simpson,&nbsp;Renea A Taylor,&nbsp;Gail P Risbridger,&nbsp;Mitchell G Lawrence","doi":"10.1002/path.6280","DOIUrl":"10.1002/path.6280","url":null,"abstract":"<p>There are diverse phenotypes of castration-resistant prostate cancer, including neuroendocrine disease, that vary in their sensitivity to drug treatment. The efficacy of BET and CBP/p300 inhibitors in prostate cancer is attributed, at least in part, to their ability to decrease androgen receptor (AR) signalling. However, the activity of BET and CBP/p300 inhibitors in prostate cancers that lack the AR is unclear. In this study, we showed that BRD4, CBP, and p300 were co-expressed in AR-positive and AR-null prostate cancer. A combined inhibitor of these three proteins, NEO2734, reduced the growth of both AR-positive and AR-null organoids, as measured by changes in viability, size, and composition. NEO2734 treatment caused consistent transcriptional downregulation of cell cycle pathways. In neuroendocrine models, NEO2734 treatment reduced <i>ASCL1</i> levels and other neuroendocrine markers, and reduced tumour growth <i>in vivo</i>. Collectively, these results show that epigenome-targeted inhibitors cause decreased growth and phenotype-dependent disruption of lineage regulators in neuroendocrine prostate cancer, warranting further development of compounds with this activity in the clinic. © 2024 The Authors. <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":"263 2","pages":"242-256"},"PeriodicalIF":7.3,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6280","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140592993","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}