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Mucinous cystic neoplasms of the pancreas and liver share a similar DNA methylation profile with mucinous ovarian tumors.
胰腺和肝脏的黏液性囊性肿瘤与卵巢黏液性肿瘤具有相似的DNA甲基化谱。
IF 5.6
2区 医学
Zoe Leoni, Teodor G Calina, Tobias Janik, Elena Grafenhorst, Eliane T Taube, Christopher Cm Neumann, BaoQing Chen, Elena I Braicu, Jalid Sehouli, Thomas Malinka, Wenzel Schöning, Johann Pratschke, George A Calin, David S Klimstra, Jamal K Benhamida, Irene Esposito, Markus Möbs, David Horst, Simon Schallenberg, David Capper, Mihnea P Dragomir
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{"title":"Mucinous cystic neoplasms of the pancreas and liver share a similar DNA methylation profile with mucinous ovarian tumors.","authors":"Zoe Leoni, Teodor G Calina, Tobias Janik, Elena Grafenhorst, Eliane T Taube, Christopher Cm Neumann, BaoQing Chen, Elena I Braicu, Jalid Sehouli, Thomas Malinka, Wenzel Schöning, Johann Pratschke, George A Calin, David S Klimstra, Jamal K Benhamida, Irene Esposito, Markus Möbs, David Horst, Simon Schallenberg, David Capper, Mihnea P Dragomir","doi":"10.1002/path.6439","DOIUrl":"https://doi.org/10.1002/path.6439","url":null,"abstract":"<p><p>The origin of mucinous cystic neoplasms (MCNs) remains a major challenge in hepato-pancreato-biliary pathology. These cystic tumors are defined by their mucinous epithelium and ovarian-like stroma, with an estimated 10% risk of progression to invasive carcinoma. The origin of the ovarian-like stroma remains a subject of debate. In this study, we conducted immunohistochemical profiling, targeted DNA sequencing, and genome-wide DNA methylation analysis on a cohort of 15 pancreatic MCNs (MCN-P) and six hepatic MCNs (MCN-L). Using immunohistochemistry and targeted DNA sequencing, we unequivocally established the diagnosis of MCN. Unsupervised DNA methylation profile analysis of reference classes of pancreatic neoplasms (11 entities and normal pancreatic tissue from 224 unique samples) revealed that MCN-P predominantly forms a distinct group. In the DNA methylation landscape of liver tumors, encompassing five tumor types and normal bile duct tissue from 136 unique samples, MCN-L demonstrated a specific methylation profile when compared with all other entities. Furthermore, within the DNA methylation landscape of ovarian tumors - featuring five tumor types, normal Fallopian tube, and normal ovarian tissue from 90 unique samples - we found that both MCN-P and MCN-L grouped with mucinous ovarian carcinoma and mucinous borderline ovarian tumors (mBOTs). Notably, low-grade MCNs exhibited greater DNA methylation similarities to mBOTs, while high-grade or invasive MCNs were primarily associated with mucinous ovarian carcinomas. When analyzing all samples together (19 tumor types and four normal tissue types, n = 430), MCNs similarly grouped with mucinous ovarian tumors and normal ovarian tissue. Additionally, in a network analysis of differentially methylated probes, MCN-P and MCN-L share significant methylation traits, closely resembling mucinous ovarian tumors. In conclusion, our findings highlight that MCN-P and MCN-L are distinct entities in the landscape of pancreatic and hepatic tumors and show DNA methylation profile similarities with mucinous ovarian tumors, suggesting a potential common origin. © 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":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482749","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}
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Analysis of IDH1 and IDH2 mutations as causes of the hypermethylator phenotype in colorectal cancer.
结直肠癌中IDH1和IDH2突变导致高甲基化表型的原因分析。
IF 5.6
2区 医学
Joseph C Ward, Melissa Morgan, James Wood, Connor Woolley, Albert Antao Nobre de Menezes, Alina Finch, Kitty Sherwood, Qiwen Huang, Chloe S Henry, Juan Fernández-Tajes, Ignacio Soriano, Steve Thorn, Isabelle Legge, James McCullagh, David Kerr, Rachel Kerr, Rahul K Hejmadi, Mark J Arends, Enric Domingo, Timothy Maughan, Chiara Bardella, Ian Tomlinson
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{"title":"Analysis of IDH1 and IDH2 mutations as causes of the hypermethylator phenotype in colorectal cancer.","authors":"Joseph C Ward, Melissa Morgan, James Wood, Connor Woolley, Albert Antao Nobre de Menezes, Alina Finch, Kitty Sherwood, Qiwen Huang, Chloe S Henry, Juan Fernández-Tajes, Ignacio Soriano, Steve Thorn, Isabelle Legge, James McCullagh, David Kerr, Rachel Kerr, Rahul K Hejmadi, Mark J Arends, Enric Domingo, Timothy Maughan, Chiara Bardella, Ian Tomlinson","doi":"10.1002/path.6446","DOIUrl":"10.1002/path.6446","url":null,"abstract":"<p><p>The CpG island methylator phenotype (CIMP) occurs in many colorectal cancers (CRCs). CIMP is closely associated with global hypermethylation and tends to occur in proximal tumours with microsatellite instability (MSI), but its origins have been obscure. A few CRCs carry oncogenic (gain-of-function) mutations in isocitrate dehydrogenase IDH1. Whilst IDH1 is an established CRC driver gene, the low frequency of IDH1-mutant CRCs (about 0.5%) has meant that the effects and molecular covariates of those mutations have not been established. We first showed computationally that IDH2 is also a CRC driver. Using multiple public and in-house CRC datasets, we then identified IDH mutations at the hotspots (IDH1 codons 132 and IDH2 codons 140 and 172) frequently mutated in other tumour types. Somatic IDH mutations were associated with BRAF mutations and expression of mucinous/goblet cell markers, but not with KRAS mutations or MSI. All IDH-mutant CRCs were CIMP-positive, mostly at a high level. Cell and mouse models showed that IDH mutation was plausibly causal for DNA hypermethylation. Whilst the aetiology of hypermethylation generally remains unexplained, IDH-mutant tumours did not form a discrete methylation subcluster, suggesting that different underlying mechanisms can converge on similar final methylation phenotypes. Although further analysis is required, IDH mutations may be the first cause of hypermethylation to be identified in a common cancer type, providing evidence that CIMP and DNA methylation represent more than aging-related epiphenomena. Cautious exploration of mutant IDH inhibitors and DNA demethylating agents is suggested in managing IDH-mutant CRCs. © 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":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367754","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}
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Circulating metabolomics reveals guanosine monophosphate synthetase (GMPS) as a novel therapeutic target in lung adenocarcinoma.
循环代谢组学揭示了鸟苷单磷酸合成酶(GMPS)是肺腺癌的一个新的治疗靶点。
IF 5.6
2区 医学
Mengjie Yu, Dou Yang, Danxia Zhu, Yue Wang, Minmin Cao, Jingfeng Zhu, Wei Zhu, Guangji Wang, Jiye Aa
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{"title":"Circulating metabolomics reveals guanosine monophosphate synthetase (GMPS) as a novel therapeutic target in lung adenocarcinoma.","authors":"Mengjie Yu, Dou Yang, Danxia Zhu, Yue Wang, Minmin Cao, Jingfeng Zhu, Wei Zhu, Guangji Wang, Jiye Aa","doi":"10.1002/path.6442","DOIUrl":"10.1002/path.6442","url":null,"abstract":"<p><p>Metabolic reprogramming is pivotal in the initiation and progression of lung adenocarcinoma (LUAD). However, a substantial gap remains in the understanding of the primary drivers of metabolic reprogramming and alterations in early-stage LUAD. Using an unbiased, large-scale metabolomics analysis of 2,531 plasma and serum samples from three independent clinical centers, we identified significant perturbations in purine metabolism that characterized reprogrammed metabolism in early-stage LUAD. Additionally, hypoxanthine (p < 0.001) and xanthine (p < 0.05) were identified as two typical early risk indicators, with odd ratios (ORs) more than 2.8 and 1.45, respectively. Guanosine monophosphate synthetase (GMPS) was identified as a pivotal factor in the early development and malignant progression of LUAD. Progression of LUAD was significantly attenuated by GMPS knockdown and markedly exacerbated by its overexpression. Further data indicated that GMPS primarily contributed to the reprogrammed metabolic phenotypes of LUAD through its enzymatic activity and subsequent production of purine nucleotides, based on the relative abundance of the labeled isotope metabolites. Collectively, dysregulated purine metabolism emerged as a key characteristic of early-stage LUAD, and targeting GMPS activity may offer a promising therapeutic potential for LUAD treatment. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332223","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}
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Genetic deletion of histone deacetylase 6 prevents peritoneal fibrosis via suppression of heat shock protein 90 deacetylation.
组蛋白去乙酰化酶6的基因缺失通过抑制热休克蛋白90去乙酰化来防止腹膜纤维化。
IF 5.6
2区 医学
Yingfeng Shi, Jinqing Li, Qin Zhong, Hui Chen, Xiaoyan Ma, Yan Hu, Yishu Wang, Daofang Jiang, Xun Zhou, Xialin Li, Shougang Zhuang, Na Liu
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{"title":"Genetic deletion of histone deacetylase 6 prevents peritoneal fibrosis via suppression of heat shock protein 90 deacetylation.","authors":"Yingfeng Shi, Jinqing Li, Qin Zhong, Hui Chen, Xiaoyan Ma, Yan Hu, Yishu Wang, Daofang Jiang, Xun Zhou, Xialin Li, Shougang Zhuang, Na Liu","doi":"10.1002/path.6436","DOIUrl":"10.1002/path.6436","url":null,"abstract":"<p><p>Peritoneal fibrosis (PF) is a serious complication contributing to ultrafiltration failure in patients undergoing peritoneal dialysis that currently lacks effective treatment strategies. Our recent studies highlighted the key role of histone deacetylase 6 (HDAC6) in the development of PF. To better understand the mechanisms underlying the involvement of HDAC6 in PF, we conducted in vivo experiments using Hdac6 KO mice and in vitro studies using human peritoneal mesothelial cells (HPMCs). Our results demonstrated that HDAC6 gene silencing improved PF and angiogenesis in vivo and altered pathological phenotypes in vitro. In Hdac6 KO mice, the key pathways regulating extracellular matrix accumulation, angiogenesis, and secretion of inflammatory cytokines (including TGFB1/SMAD3, HIF-1α/VEGFR-2/MAPK3/MAPK1, and TLR4/NF-κB pathways) were inhibited. We also identified heat shock protein 90 (HSP90) as the substrate of HDAC6 in both PF mice and HPMCs and demonstrated that HDAC6 exerted its regulatory function in PF through the deacetylation of HSP90. Overall, our study provides novel insights into the critical role of the HDAC6-HSP90 interplay in PF using Hdac6 KO mice. We identify HSP90 as an essential substrate through which HDAC6 exerts its function in PF, providing an experimental basis for the development of novel therapeutic strategies. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332224","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}
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Development and characterisation of improved unifocal primary mouse lung cancer models with metastatic potential.
具有转移潜力的改进的单灶原发性小鼠肺癌模型的发展和特征。
IF 5.6
2区 医学
Ana-Rita Pedrosa, Alejandro Castillo-Kauil, Yuliia Kravchuk, Louise Reynolds, Bruce Williams, David Moore, Cameron Lang, Srinivas Allanki, Eleni Maniati, Alexandros Hardas, Jozafina Haj, Rebecca Drake, Julie Cleaver, Julie Foster, Jana Kim, Ester Stern, Jane Sosabowski, Gilbert O Fruhwirth, Erik Sahai, Ori Wald, Kairbaan Hodivala-Dilke
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{"title":"Development and characterisation of improved unifocal primary mouse lung cancer models with metastatic potential.","authors":"Ana-Rita Pedrosa, Alejandro Castillo-Kauil, Yuliia Kravchuk, Louise Reynolds, Bruce Williams, David Moore, Cameron Lang, Srinivas Allanki, Eleni Maniati, Alexandros Hardas, Jozafina Haj, Rebecca Drake, Julie Cleaver, Julie Foster, Jana Kim, Ester Stern, Jane Sosabowski, Gilbert O Fruhwirth, Erik Sahai, Ori Wald, Kairbaan Hodivala-Dilke","doi":"10.1002/path.6435","DOIUrl":"https://doi.org/10.1002/path.6435","url":null,"abstract":"<p><p>Lung cancer is the leading cause of cancer-related death globally. To better understand the biology of lung cancer, mouse models have been developed using either tail vein-injected tumour cell lines or genetically modified mice. The current gold-standard models typically present with multiple lung foci. However, although these models are widely used, their correlation with human disease are limited, as early-stage human lung cancer usually presents as a single lesion rather than multiple foci. Additionally, a major challenge of using multifocal lung tumour models is the difficulty in distinguishing primary lung tumours from intrathoracic metastasis and lethal levels of lung congestion before distant metastases develop. Here, we present a refined and detailed surgical method in which murine tumour cells [Lewis lung carcinoma (LLC), alveogenic lung carcinoma (CMT), or Kras/Trp53-KP mutant cells] were injected directly into the left lung lobe of C57BL/6 mice, or, alternatively, adenoviral-Cre or adenoviral-FlpO was administered directly into the left lung lobe of Kras<sup>LSL-G12D</sup>;Trp53<sup>fl/fl</sup> or Kras<sup>FSF-G12D</sup>;Trp53<sup>frt/frt</sup> (KP) mice, respectively. This method generated unifocal primary left lung lobe tumours with traceable spread to local and distant sites. A cross-comparison of the unifocal models described commonalties and differences between LLC, CMT, KP cells, and adenoviral-Cre or -FlpO methods in terms of timings for primary lung tumour growth and traceable spread to local and distant sites, histological analysis of CD3 and CD11b immune cell infiltration, and Picrosirius Red analysis of extracellular matrix complexity. Lastly, the frequency of clinical histopathological features typical of human lung cancer were assessed across the unifocal mouse models to provide a direct comparison with human lung cancer. Overall, this study details a refined and reproducible protocol for intralobular lung injection to generate unifocal lung cancer models that resemble key features of human lung cancer. This approach can be applied to other lung cancer initiation strategies. The cross-comparative histological analysis across the models tested here offers a valuable resource to aid researchers in selecting the most appropriate next-generation unifocal lung cancer models for their specific research needs. © 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":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324041","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}
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Soft tissue sarcoma with MN1 gene fusions: a report of three cases with aggressive clinical behavior.
MN1基因融合软组织肉瘤:3例侵袭性临床表现报告。
IF 5.6
2区 医学
Carla Saoud, Josephine K Dermawan, Narasimhan P Agaram, Marc Rosenblum, Tejus A Bale, Cristina R Antonescu
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{"title":"Soft tissue sarcoma with MN1 gene fusions: a report of three cases with aggressive clinical behavior.","authors":"Carla Saoud, Josephine K Dermawan, Narasimhan P Agaram, Marc Rosenblum, Tejus A Bale, Cristina R Antonescu","doi":"10.1002/path.6441","DOIUrl":"https://doi.org/10.1002/path.6441","url":null,"abstract":"<p><p>Canonical MN1 fusions with either BEND2 or CXXC5 gene partners represent the molecular hallmark of astroblastoma, a stand-alone group among central nervous system (CNS) high-grade neuroepithelial tumors based on their distinct methylation profile. Outside the CNS, MN1 fusions have been rarely reported, mostly with nonrecurrent gene partners. Herein, we present three cases of soft tissue sarcomas harboring MN1 gene rearrangements, two of which had MN1 (exon 1)::CXXC5 (exon 2) gene fusion and the last had MN1 (exon 1)::ZFP64 (exon 2) gene fusion. The tumors occurred in young to middle-aged adults (two females and one male) and involved the preauricular, abdominal, and sacral soft tissue. Patients with MN1::CXXC5 fusion had widespread metastatic disease at presentation. Histologically, tumors with the MN1::CXXC5 fusion showed nests of monomorphic round and focally spindled cells, compatible with round cell sarcoma, while MN1::ZNFP64 fused tumors exhibited monomorphic spindle cells arranged in storiform and short fascicular patterns. Mitotic activity was brisk in all cases; however, tumor necrosis was minimal to absent. MN1::CXXC5 fused tumors exhibited CD99 and S100 expression, an immunophenotype that is not specific for a particular line of differentiation and is distinct from astroblastoma. MN1::ZNFP64 were positive for p63 and androgen receptor (AR) expression. Low tumor mutation burden and low levels of genome alteration were seen in all cases. DNA methylation profiling showed that the three cases could not be classified into any of the current methylation classes using the DKFZ classifier for sarcomas (version 12.2) or CNS tumors (version 12.8). T-distributed Stochastic Neighbor Embedding analysis revealed that the three sarcomas with MN1 gene rearrangement clustered together, forming a distinct group, in close proximity to epithelioid sarcoma, separate from CNS high-grade neuroepithelial tumor with MN1 alterations. In our series, all three cases exhibited aggressive clinical behavior; notably, the two patients with MN1::CXXC5 gene fusion sarcomas succumbed to the disease within 20 to 23 months. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273812","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}
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Post-COVID-19 condition: clinical phenotypes, pathophysiological mechanisms, pathology, and management strategies.
covid -19后的情况:临床表型、病理生理机制、病理和管理策略。
IF 5.6
2区 医学
Larissa E Vlaming-van Eijk, Guolu Tang, Arno R Bourgonje, Wilfred F A den Dunnen, Jan-Luuk Hillebrands, Harry van Goor
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{"title":"Post-COVID-19 condition: clinical phenotypes, pathophysiological mechanisms, pathology, and management strategies.","authors":"Larissa E Vlaming-van Eijk, Guolu Tang, Arno R Bourgonje, Wilfred F A den Dunnen, Jan-Luuk Hillebrands, Harry van Goor","doi":"10.1002/path.6443","DOIUrl":"10.1002/path.6443","url":null,"abstract":"<p><p>Post-COVID-19 condition (PCC), also known as long COVID, is a complex multiple organ system condition that can develop and persist for months after acute COVID-19. PCC encompasses a wide range of symptoms, resulting in heterogeneous clinical manifestations. These manifestations likely arise from diverse underlying pathophysiological mechanisms, which, in turn, are influenced by risk factors such as age, sex, and comorbidities. To this end, characterising clinical phenotypes of PCC is essential for deepening our understanding of its (potentially) distinct pathophysiological mechanisms and for advancing diagnostic and patient-tailored management strategies. PCC is thought to result from a complex interaction of various pathophysiological mechanisms, leading to functional and structural pathological alterations across multiple organ systems. Investigating these alterations is critical to improving our currently incomplete understanding of PCC's complex pathophysiology. This review provides an overview of the main clinical phenotypes of PCC, characterises these phenotypes by examining symptoms and signs, as well as the associated risk factors. The main hypothesised pathophysiological mechanisms are discussed by outlining the current knowledge on PCC pathology, focussing on the most commonly affected organ systems. Current PCC management includes supportive care such as physiotherapy and the repurposing of existing drugs primarily targeting persistence of SARS-CoV-2 (e.g. antivirals, monoclonal antibodies) and immune dysfunction (e.g. antiinflammatory drugs, immunomodulators). To date, prevention of SARS-CoV-2 infection remains critical, which can be achieved through effective public health measures and vaccination strategies. Finally, this review highlights current knowledge gaps and proposes future research directions to advance the understanding and treatment of PCC. © 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":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256929","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}
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Resistance mechanisms and clonal dynamics in mantle cell lymphoma treated with sequential BTKi and venetoclax therapy.
连续BTKi和venetoclax治疗套细胞淋巴瘤的耐药机制和克隆动力学。
IF 5.6
2区 医学
Tamás László, László Imre Pinczés, Bence Bátai, Luca Varga, Botond Timár, Anita Gulyás, Ilona Tárkányi, Márk Plander, Zsolt Nagy, Péter Rajnics, Miklós Egyed, Zsuzsa Molnár, János Rottek, András Masszi, Péter Tamáska, Róbert Szász, Árpád Illés, Donát Alpár, Ferenc Magyari, Csaba Bödör
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{"title":"Resistance mechanisms and clonal dynamics in mantle cell lymphoma treated with sequential BTKi and venetoclax therapy.","authors":"Tamás László, László Imre Pinczés, Bence Bátai, Luca Varga, Botond Timár, Anita Gulyás, Ilona Tárkányi, Márk Plander, Zsolt Nagy, Péter Rajnics, Miklós Egyed, Zsuzsa Molnár, János Rottek, András Masszi, Péter Tamáska, Róbert Szász, Árpád Illés, Donát Alpár, Ferenc Magyari, Csaba Bödör","doi":"10.1002/path.6434","DOIUrl":"https://doi.org/10.1002/path.6434","url":null,"abstract":"<p><p>In recent years, targeted therapies have become the standard of care for refractory/relapsed mantle cell lymphoma (MCL). Although the mutational profile of MCL has been extensively studied, there is a lack of understanding of resistance mechanisms and genetic factors that impact the response to novel treatments. Since patients relapsing on targeted treatment experience poor clinical outcomes, understanding the genetic foundation of resistance mechanisms in MCL is essential. In this study, we aimed to scrutinize the copy number profile and clonal dynamics of double-resistant MCL patients treated sequentially with Bruton's tyrosine kinase inhibitor (BTKi) and venetoclax using low-coverage whole genome sequencing (lcWGS). Samples obtained after systemic therapy showed more copy number alterations (CNAs) (p = 0.039; Wilcoxon) compared to samples collected before treatment initiation. Patients showing early progression on BTKi demonstrated CNAs affecting cytobands encompassing the coding regions of NOTCH1, TRAF2, BIRC2, BIRC3, and ATM. A deletion in chromosome 9p21.3 was identified in two out of three venetoclax-resistant patients. For patient MCL2, progressing on ibrutinib but showing venetoclax resistance, a 9p21.3 deletion was found throughout the disease course, with acquired SMARCA4-del(19)(p13.3-q13.11) and DLC1-del(8)(p23.2-q11.1) observed at relapse, highlighting their role in disease progression and therapy resistance. Using lcWGS, an innovative genome-wide approach, this study revealed novel putative primary and acquired resistance mechanisms in BTKi and venetoclax double-resistant MCL 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":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075079","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}
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Mucinous cystic neoplasms and simple mucinous cysts are two distinct precursors of pancreatic cancer: clinicopathological, genomic, and transcriptomic characterization.
粘液囊性肿瘤和单纯性粘液囊肿是胰腺癌的两种不同的前体:临床病理学、基因组学和转录组学特征。
IF 5.6
2区 医学
Antonio Pea, Michele Bevere, Anastasios Gkountakos, Davide Pasini, Denise Fiorini, Andrea Mafficini, Stela Golovco, Michele Simbolo, Serena Pedron, Concetta Sciammarella, Paola Mattiolo, Aldo Mombello, Manuela Villanova, Carlotta Franzina, Francesca Masetto, Calogero Ciulla, Nicola Sperandio, Kohei Fujikura, Masha S Ahadi, Jaswinder S Samra, Amber L Johns, Joanne Verheij, Martijn W J Stommel, Hjalmar van Santvoort, Leonor Schubert Santana, Giuseppe Malleo, Michele Milella, Lodewijk A A Brosens, Laura D Wood, David K Chang, Riccardo De Robertis, Mirko D'Onofrio, Anthony J Gill, Roberto Salvia, Vincenzo Corbo, Rita T Lawlor, Aldo Scarpa, Claudio Luchini
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{"title":"Mucinous cystic neoplasms and simple mucinous cysts are two distinct precursors of pancreatic cancer: clinicopathological, genomic, and transcriptomic characterization.","authors":"Antonio Pea, Michele Bevere, Anastasios Gkountakos, Davide Pasini, Denise Fiorini, Andrea Mafficini, Stela Golovco, Michele Simbolo, Serena Pedron, Concetta Sciammarella, Paola Mattiolo, Aldo Mombello, Manuela Villanova, Carlotta Franzina, Francesca Masetto, Calogero Ciulla, Nicola Sperandio, Kohei Fujikura, Masha S Ahadi, Jaswinder S Samra, Amber L Johns, Joanne Verheij, Martijn W J Stommel, Hjalmar van Santvoort, Leonor Schubert Santana, Giuseppe Malleo, Michele Milella, Lodewijk A A Brosens, Laura D Wood, David K Chang, Riccardo De Robertis, Mirko D'Onofrio, Anthony J Gill, Roberto Salvia, Vincenzo Corbo, Rita T Lawlor, Aldo Scarpa, Claudio Luchini","doi":"10.1002/path.6437","DOIUrl":"https://doi.org/10.1002/path.6437","url":null,"abstract":"<p><p>Mucinous cystic neoplasms (MCNs) of the pancreas are macroscopic precursors of pancreatic cancer. A similar cystic lesion but lacking the ovarian-type subepithelial stroma has been recently defined as a simple mucinous cyst (SMC); however, its nature remains unclear. This study aims to define the clinicopathological and molecular profiles of a cohort of MCNs and SMCs of the pancreas and their associated invasive carcinoma. Overall, 23 cases were identified, comprising 19 MCNs and 4 SMCs with co-occurring invasive carcinoma. A multiregional (two samples from each cystic lesion and one from the adenocarcinoma) DNA and RNA sequencing approach was used. The key findings can be summarized as follows: (1) Molecular association: In 22/23 cases (95.7%), the concomitant mucinous cyst and invasive carcinoma shared specific genomic alterations, establishing for the first time that SMC is a true precursor of pancreatic cancer. (2) Clinical behavior: carcinomas arising from SMC appeared to be more aggressive than those arising from MCN. (3) Mutational profile: both cyst types showed significant similarities to conventional pancreatic ductal adenocarcinoma (PDAC), with KRAS and TP53 the most commonly altered genes. (4) Intracystic heterogeneity: while most molecular alterations were present in both analyzed cystic areas, RNF43 showed the highest heterogeneity. (5) CDKN2A: its alterations were predominantly restricted to the invasive component, suggesting a role in driving the invasion in a subset of cases. CNKN2A may also serve as a potential biomarker for identifying high-risk cysts. (6) RNAseq: most cases showed a switch from the classical to the basal transcriptome subtype during the progression from cystic neoplasms to invasive cancers. These findings establish SMCs as new precursors of pancreatic cancer and provide critical insights into the tumorigenesis of MCNs, with potential immediate implications for tumor taxonomy and clinical management. © 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":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075070","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}
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NSD1 mutation status determines metabolic inhibitor sensitivity in head and neck squamous cell carcinomas by regulating mitochondrial respiration
NSD1突变状态通过调节线粒体呼吸决定头颈部鳞状细胞癌代谢抑制剂的敏感性。
IF 5.6
2区 医学
Shouyi Tang, Qing Wang, Zhen Wang, Luyao Cai, Dan Pan, Jing Li, Qianming Chen, Yu Zhou, Ying-Qiang Shen
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{"title":"NSD1 mutation status determines metabolic inhibitor sensitivity in head and neck squamous cell carcinomas by regulating mitochondrial respiration","authors":"Shouyi Tang, Qing Wang, Zhen Wang, Luyao Cai, Dan Pan, Jing Li, Qianming Chen, Yu Zhou, Ying-Qiang Shen","doi":"10.1002/path.6430","DOIUrl":"10.1002/path.6430","url":null,"abstract":"<p>Head and neck squamous cell carcinomas (HNSCCs) are the most common malignant tumors in the head and neck region, characterized by a high recurrence rate and early metastasis. Despite advances in treatment, patient outcomes and prognosis remain poor, highlighting the urgent need for new therapeutic strategies. Recent research has increasingly focused on targeting glucose metabolism as a therapeutic strategy for cancer, revealing multiple promising targets and potential drugs. However, the metabolic heterogeneity among tumors leads to variable sensitivity to metabolic inhibitors in different patients, limiting their clinical utility. In this study, we employed bioinformatics analysis, cell experiments, animal models, and multi-omics approaches to reveal differences in glucose metabolism phenotypes among HNSCC patients and elucidated the underlying molecular mechanisms driving these differences. Our findings showed that <i>NSD1</i> mutation status affects the glucose metabolism phenotype in HNSCC, with <i>NSD1</i> wild-type HNSCC exhibiting higher mitochondrial respiration and <i>NSD1</i> mutant HNSCC showing weaker mitochondrial respiration but enhanced glycolysis. We further demonstrated that <i>NSD1</i> regulates mitochondrial respiration in HNSCC via epigenetic modulation of the <i>TGFB2</i>/<i>PPARGC1A</i> signaling axis. Additionally, we found that <i>NSD1</i> wild-type HNSCC is more sensitive to mitochondrial respiration inhibitors, whereas <i>NSD1</i> mutant HNSCC shows increased sensitivity to glycolysis inhibitors. In summary, we found that <i>NSD1</i> can epigenetically regulate the <i>TGFB2</i>/<i>PPARGC1A</i> axis to modulate mitochondrial respiration and sensitivity to metabolic inhibitors in HNSCC. These findings suggest a novel strategy for selecting metabolic inhibitors for HNSCC based on the <i>NSD1</i> gene status of patients. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 3","pages":"306-321"},"PeriodicalIF":5.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075077","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}
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