The Journal of Pathology最新文献

{"title":"Unveiling the intriguing relationship: oncogenic KRAS, morphological shifts, and mutational complexity in pancreatic mucinous cystic neoplasms.","authors":"Schulte, Annika Beck, Ralf Marienfeld, Ninel Azoitei, Thomas Barth, Alica Beutel, Vladimir Benes, Markus Büchler, Nadine Gaisa, Katja Kilani, Nathalia Giese, Christoph W Michalski, Peter Möller, Lukas Perkhofer, Tobias Rausch, Stefan Repky, Elodie Roger, Jeanette Scheible, Thomas Seufferlein, Peter Schirmacher, Berger, Thilo Hackert, Alexander Kleger","doi":"10.1002/path.6397","DOIUrl":"https://doi.org/10.1002/path.6397","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) often arises from preexisting cystic lesions such as intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN). This study investigated the molecular heterogeneity and mutational landscape of MCN in relation to PDAC, highlighting the significance of KRAS mutations in tumor progression. Utilizing targeted next-generation sequencing on low-grade MCN and invasive PDAC samples, we identified a substantial overlap in mutational profiles, particularly mutations in KRAS, TP53, and FBXW7. Specifically, 69.2% of MCN exhibited somatic mutations, with KRAS mutations being a predominant oncogenic driver. The characterization of mutant versus wildtype KRAS variant allele frequencies (VAF) indicated higher mutation levels in PDAC compared to MCN, suggesting an evolutionary trajectory toward malignancy. Further histological analysis of 12 additional MCN cases revealed significant intratumor heterogeneity, with variant KRAS mutation distributions correlating with distinct cellular morphologies and dysplastic features. Additionally, we explored the potential of liquid biopsies, demonstrating a concordance rate of 71.4% for KRAS mutation detection in circulating tumor DNA (ctDNA) relative to tissue biopsies across cohorts. Our findings underscore the relevance of evaluating KRAS mutations-herein referred to as VAF per microdissected region-as they relate to histopathological markers of dysplasia, contributing to improved stratification of pancreatic lesions and facilitating personalized treatment strategies. In conclusion, this comprehensive analysis of MCN highlights the importance of KRAS as a crucial biomarker for both malignant progression and therapeutic decision-making in pancreatic pathology. Ultimately, our study suggests that characterizing the mutational landscape and histological features of MCN can enhance early detection and intervention strategies for at-risk patients. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187629","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":"Downregulation of AATK enhances susceptibility to ferroptosis by promoting endosome recycling in gefitinib-resistant lung cancer cells.","authors":"Wei-Chang Lee, Sin-Hua Moi, Sheau-Fang Yang, Ho-Hsing Tseng, Yu-Peng Liu","doi":"10.1002/path.6393","DOIUrl":"https://doi.org/10.1002/path.6393","url":null,"abstract":"<p><p>Ferroptosis has been characterised by disruption of the cell membrane through iron-related lipid peroxidation. However, regulation of iron homeostasis in lung cancer cells that are resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains unclear. Transcriptome analysis identified a significant downregulation of apoptosis-associated tyrosine kinase (AATK) mRNA expression in gefitinib-resistant PC9 (PC9-GR) cells, which were found to be more susceptible to ferroptosis inducers. An in-depth analysis of publicly available datasets revealed that downregulation of AATK mRNA was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma. Knockdown of AATK-sensitised PC9, HCC827, and H441 cells to the ferroptosis inducer RSL3, whereas ectopic expression of AATK reduced RSL3-induced cell death in PC9-GR and HCC827-GR cells. Compared to PC9 cells, PC9-GR cells exhibited higher transferrin uptake, endosome recycling rate, and increased intracellular iron levels. Blocking iron transport reduced RSL3-induced ferroptosis in PC9-GR cells. Mechanistic studies showed that AATK localised to both early and recycling endosomes. Knockdown of AATK facilitated endosome recycling and elevated intracellular ferrous iron (Fe²⁺) levels in PC9 cells. Conversely, ectopic expression of AATK delayed endosome recycling and reduced intracellular Fe²⁺ levels in PC9-GR cells. Inhibition of AATK downregulation-induced iron accumulation decreased RSL3-induced ferroptosis. Taken together, our study indicates that the downregulation of AATK contributes to endosome recycling and iron accumulation, leading to an increased susceptibility to ferroptosis in EGFR-TKI-resistant lung cancer cells. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051087","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":"Extracellular matrix cancer-associated fibroblasts promote stromal fibrosis and immune exclusion in triple-negative breast cancer","authors":"Xunxi Lu,&nbsp;Zongchao Gou,&nbsp;Hong Chen,&nbsp;Li Li,&nbsp;Fei Chen,&nbsp;Chunjuan Bao,&nbsp;Hong Bu,&nbsp;Zhang Zhang","doi":"10.1002/path.6395","DOIUrl":"10.1002/path.6395","url":null,"abstract":"<p>The impact of high heterogeneity of cancer-associated fibroblasts (CAFs) on triple-negative breast cancer (TNBC) immunotherapy response has not been fully elucidated, restricting progress in precision immuno-oncology. We integrated single-cell transcriptomic data from 18 TNBC patients and analyzed fibroblast subpopulations. Extracellular matrix CAFs (ecmCAFs) were identified as a fibroblast subpopulation with distinct ECM-associated characteristics. The ecmCAFs were significantly enriched in TNBC patients with residual disease after neoadjuvant immunotherapy and contributed to a fibrotic tumor microenvironment and T-cell exclusion. Secreted phosphoprotein 1 (<i>SPP1</i>) positive macrophages (SPP1⁺ Mφs) were closely localized to ecmCAFs and produced more transforming growth factor beta (<i>TGFB1</i>), interleukin 1 beta (<i>IL1B</i>), and <i>SPP1</i> under hypoxic conditions. SPP1⁺ Mφs were found to facilitate the differentiation of normal breast fibroblasts to ecmCAFs, thus promoting ECM remodeling and stromal fibrosis. Our work revealed the critical role of ecmCAFs in generating a desmoplastic architecture and driving immunosuppression in TNBC. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 3","pages":"385-399"},"PeriodicalIF":5.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021419","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":"Assessing spatial sequencing and imaging approaches to capture the molecular and pathological heterogeneity of archived cancer tissues","authors":"Tuan Vo,&nbsp;P Prakrithi,&nbsp;Kahli Jones,&nbsp;Sohye Yoon,&nbsp;Pui Yeng Lam,&nbsp;Yung-Ching Kao,&nbsp;Ning Ma,&nbsp;Samuel X Tan,&nbsp;Xinnan Jin,&nbsp;Chenhao Zhou,&nbsp;Joanna Crawford,&nbsp;Shaun Walters,&nbsp;Ishaan Gupta,&nbsp;Peter H Soyer,&nbsp;Kiarash Khosrotehrani,&nbsp;Mitchell S Stark,&nbsp;Quan Nguyen","doi":"10.1002/path.6383","DOIUrl":"10.1002/path.6383","url":null,"abstract":"<p>Spatial transcriptomics (ST) offers enormous potential to decipher the biological and pathological heterogeneity in precious archival cancer tissues. Traditionally, these tissues have rarely been used and only examined at a low throughput, most commonly by histopathological staining. ST adds thousands of times as many molecular features to histopathological images, but critical technical issues and limitations require more assessment of how ST performs on fixed archival tissues. In this work, we addressed this in a cancer-heterogeneity pipeline, starting with an exploration of the whole transcriptome by two sequencing-based ST protocols capable of measuring coding and non-coding RNAs. We optimised the two protocols to work with challenging formalin-fixed paraffin-embedded (FFPE) tissues, derived from skin. We then assessed alternative imaging methods, including multiplex RNAScope single-molecule imaging and multiplex protein imaging (CODEX). We evaluated the methods’ performance for tissues stored from 4 to 14 years ago, covering a range of RNA qualities, allowing us to assess variation. In addition to technical performance metrics, we determined the ability of these methods to quantify tumour heterogeneity. We integrated gene expression profiles with pathological information, charting a new molecular landscape on the pathologically defined tissue regions. Together, this work provides important and comprehensive experimental technical perspectives to consider the applications of ST in deciphering the cancer heterogeneity in archived tissues. © 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":"274-288"},"PeriodicalIF":5.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6383","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021408","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":"Alternative driver pathways in peripheral nerve sheath tumors – including DICER1 and/or KRAS alterations","authors":"Hsin-Yi Chang,&nbsp;Carla Saoud,&nbsp;Dianne Torrence,&nbsp;William Tap,&nbsp;Ping Chi,&nbsp;Cristina R Antonescu","doi":"10.1002/path.6391","DOIUrl":"10.1002/path.6391","url":null,"abstract":"<p><i>DICER1</i>-associated sarcoma is an emerging entity, defined by either somatic or germline dicer 1, ribonuclease III (<i>DICER1</i>) mutations and sharing characteristic morphologic features irrespective of the site of origin. In addition to the <i>DICER1</i> driver mutation, concurrent genomic alterations, including tumor protein 53 (<i>TP53</i>) inactivation and RAS pathway activation, are frequently detected. Tumors that morphologically resemble malignant peripheral nerve sheath tumor (MPNST) have rarely been reported among DICER1 sarcomas and often pose diagnostic challenges. This study was prompted by a case involving morphologic features of MPNST, which harbored co-existing <i>DICER1</i> and hotspot <i>KRAS</i> mutations. Hence, we investigated the incidence of these alterations in PNST from our molecular database compared to the genomic and morphologic spectrum of <i>DICER1</i>-mutant sarcomas. In total, we identified three cases diagnosed as MPNST with co-existing <i>DICER1</i>, ATRX chromatin remodeler (<i>ATRX</i>), and <i>KRAS</i> G12V/A alterations occurring in brain, cerebellopontine angle, and intra-abdominal sites. Two additional cases each of MPNSTs and neurofibromas were identified with hotspot <i>KRAS</i> mutations. All five MPNSTs lacked canonical neurofibromin 1 (<i>NF1</i>)/neurofibromin 2 (<i>NF2</i>) alterations, displaying a classic morphologic appearance with fascicular monomorphic spindle cells and followed a diverse clinical behavior. Among the 38 <i>DICER1</i>-associated sarcomas in our database, eight (21%) had secondary <i>KRAS</i> hotspot mutations, all composed of monomorphic spindle and/or round cells, including three with an MPNST-like histology. In contrast, all 10 (26%) <i>DICER1</i>-mutant sarcomas with <i>TP53</i> mutations showed a pleomorphic phenotype. The DNA-based methylation profile of our index case clustered within the group of sarcomas with <i>DICER1</i> alterations. Our results highlight a small subset of MPNST associated with <i>DICER1</i> and/or <i>KRAS</i> mutations. However, their relationship with conventional MPNST remains to be determined in larger studies. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 3","pages":"372-384"},"PeriodicalIF":5.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021324","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":"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}

{"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}

{"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⁺-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}

{"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}

{"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_peakT_end intervals and premature ventricular contractions. In adult mouse cardiomyocytes, Klotho treatment restricted systolic calcium (Ca²⁺) release and cell shortening disturbances after MI. Klotho prevented increased diastolic Ca²⁺ leak and pro-arrhythmogenic events in PMI mice by blocking activation of the Ca²⁺/calmodulin-dependent kinase type II (CaMKII) pathway, preventing ryanodine receptor type 2 (RyR₂) hyperphosphorylation. In conclusion, Klotho supplementation protected against functional and structural cardiac remodelling and ameliorated ventricular arrhythmic events by preventing intracardiomyocyte Ca²⁺ 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}