Pub Date : 2025-10-15DOI: 10.1016/j.prp.2025.156272
Peng Luo , Shijie Dai , Xingyuan Xu , Gaoyu Liu, Fulong Wang, Jialun Li, Qin Xiong, Yang Wang, Chunmeng Shi
Hepatocellular carcinoma (HCC) is a common malignancy with high risk of recurrence and metastasis. Growing evidences reveal that aberrant mRNA splicing represents a crucial molecular characteristic of cancer, which produces numerous and complex transcript variants to drive cancer development and progression. Here, we identified the splicing factor U2AF2 as a promising oncogenic biomarker in HCC, and subsequently explored its biological role and mechanism. Through bioinformatics analysis and clinical verification, U2AF2 was found to be significantly elevated in HCC, showing a strong correlation with the pathological grade and patient outcomes. Subsequent investigations demonstrated that U2AF2 promoted HCC growth and metastasis both in vitro and in vivo. Mechanically, U2AF2 exerted its oncogenic functions by cooperating with SRSF1 to bind to the pre-mRNA of CCND1(Cyclin D1) and facilitate the generation of CCND1b isoform. Moreover, U2AF2 could potentially be utilized for the prediction of chemo-responsiveness. Its depletion sensitized HCC cells to Doxorubicin, a first-line chemotherapy agent for advanced HCC patients. Altogether, this study deepens our understanding of U2AF2 in mRNA splicing and provides a potential therapeutic target for HCC.
{"title":"U2AF2 drives malignant progression and chemo-resistance in hepatocellular carcinoma through cooperating with SRSF1 to modulate CCND1 splice-variant expression","authors":"Peng Luo , Shijie Dai , Xingyuan Xu , Gaoyu Liu, Fulong Wang, Jialun Li, Qin Xiong, Yang Wang, Chunmeng Shi","doi":"10.1016/j.prp.2025.156272","DOIUrl":"10.1016/j.prp.2025.156272","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a common malignancy with high risk of recurrence and metastasis. Growing evidences reveal that aberrant mRNA splicing represents a crucial molecular characteristic of cancer, which produces numerous and complex transcript variants to drive cancer development and progression. Here, we identified the splicing factor U2AF2 as a promising oncogenic biomarker in HCC, and subsequently explored its biological role and mechanism. Through bioinformatics analysis and clinical verification, U2AF2 was found to be significantly elevated in HCC, showing a strong correlation with the pathological grade and patient outcomes. Subsequent investigations demonstrated that U2AF2 promoted HCC growth and metastasis both in vitro and in vivo. Mechanically, U2AF2 exerted its oncogenic functions by cooperating with SRSF1 to bind to the pre-mRNA of CCND1(Cyclin D1) and facilitate the generation of CCND1b isoform. Moreover, U2AF2 could potentially be utilized for the prediction of chemo-responsiveness. Its depletion sensitized HCC cells to Doxorubicin, a first-line chemotherapy agent for advanced HCC patients. Altogether, this study deepens our understanding of U2AF2 in mRNA splicing and provides a potential therapeutic target for HCC.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"276 ","pages":"Article 156272"},"PeriodicalIF":3.2,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145364457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The testis is an immune-privileged organ due to its lack of functional human leukocyte antigen (HLA) class I expression. However, the expression status of HLA class I in testicular seminoma, which is characterized histologically by lymphocytic infiltration, remains unclear.
Materials and methods
We performed immunohistochemistry to evaluate HLA class I expression and its spatial relationship with CD8-positive cells in 20 cases of stage I seminoma. Each specimen was scored manually and further analyzed using the HALO image analysis platform.
Results
Manual scoring and HALO analysis showed 80 % concordance. HLA class I expression was positive in 13 cases (65 %). Tumors were classified into three categories based on the expression levels. The number of infiltrating CD8-positive cells was significantly correlated with HLA class I expression. Spatial analysis revealed that tumors with higher HLA class I expression had shorter distances between HLA class I–positive tumor cells and CD8-positive cells.
Conclusion
Seminoma cells expressing HLA class I tended to be located in close proximity to CD8-positive T cells, suggesting a spatial relationship that might influence the tumor immune microenvironment.
{"title":"Automated spatial analysis reveals proximity of human leukocyte antigen class I-positive tumor cells and CD8-positive cells of the tumor microenvironment in stage I seminoma","authors":"Takuto Ogasawara , Terufumi Kubo , Kenta Sasaki , Naoki Shijubou , Rena Morita , Kenji Murata , Kohei Hashimoto , Tomohide Tsukahara , Hiroko Asanuma , Toshihiko Torigoe , Reiko Watanabe , Naoya Masumori , Yoshihiko Hirohashi","doi":"10.1016/j.prp.2025.156270","DOIUrl":"10.1016/j.prp.2025.156270","url":null,"abstract":"<div><h3>Background</h3><div>The testis is an immune-privileged organ due to its lack of functional human leukocyte antigen (HLA) class I expression. However, the expression status of HLA class I in testicular seminoma, which is characterized histologically by lymphocytic infiltration, remains unclear.</div></div><div><h3>Materials and methods</h3><div>We performed immunohistochemistry to evaluate HLA class I expression and its spatial relationship with CD8-positive cells in 20 cases of stage I seminoma. Each specimen was scored manually and further analyzed using the HALO image analysis platform.</div></div><div><h3>Results</h3><div>Manual scoring and HALO analysis showed 80 % concordance. HLA class I expression was positive in 13 cases (65 %). Tumors were classified into three categories based on the expression levels. The number of infiltrating CD8-positive cells was significantly correlated with HLA class I expression. Spatial analysis revealed that tumors with higher HLA class I expression had shorter distances between HLA class I–positive tumor cells and CD8-positive cells.</div></div><div><h3>Conclusion</h3><div>Seminoma cells expressing HLA class I tended to be located in close proximity to CD8-positive T cells, suggesting a spatial relationship that might influence the tumor immune microenvironment.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"276 ","pages":"Article 156270"},"PeriodicalIF":3.2,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-09DOI: 10.1016/j.prp.2025.156255
Xiaoyuan Ma , Zhihua Shao , Junyu Deng , Guangze Chen , Junchi Ma , Zeren Chen , Yu Zhang , Peng Han , Junsong Liu , Shan Gao , Yuan Shao , Fang Sui
Emerging evidence highlights the role of Endoplasmic Reticulum Membrane Protein Complex (EMC) subunits in tumorigenesis, yet the function of EMC8 (Endoplasmic Reticulum Membrane Protein Complex Subunit 8) in Head and Neck Squamous Cell Carcinoma (HNSCC) remains elusive. In this study, we found EMC8 is significantly upregulated in HNSCC tissues compared to adjacent normal tissues, at both mRNA and protein levels. Kaplan-Meier survival analyses demonstrated that high EMC8 expression is associated with poorer overall survival, disease-specific survival, and progression-free interval in HNSCC patients. Further exploration into the tumor microenvironment showed that EMC8 expression negatively correlates with the infiltration of multiple immune cells, particularly CD8 + T cells, which was validated in clinical samples where high EMC8 expression corresponded to reduced CD8 + T cell infiltration. Additionally, single-cell RNA sequencing data indicated that EMC8 expression is positively associated with dedifferentiation, hypoxia, and stemness properties of HNSCC cells. Collectively, EMC8 upregulation in HNSCC correlates with poor prognosis, reduced CD8 + T cell infiltration, and aggressive phenotypes, positioning it as a potential prognostic marker with mechanistic links to immune evasion and malignancy warranting deeper exploration.
{"title":"EMC8 expression in head and neck squamous cell carcinoma: Implications for poor prognosis and deficient CD8+ T cell infiltration","authors":"Xiaoyuan Ma , Zhihua Shao , Junyu Deng , Guangze Chen , Junchi Ma , Zeren Chen , Yu Zhang , Peng Han , Junsong Liu , Shan Gao , Yuan Shao , Fang Sui","doi":"10.1016/j.prp.2025.156255","DOIUrl":"10.1016/j.prp.2025.156255","url":null,"abstract":"<div><div>Emerging evidence highlights the role of Endoplasmic Reticulum Membrane Protein Complex (EMC) subunits in tumorigenesis, yet the function of EMC8 (Endoplasmic Reticulum Membrane Protein Complex Subunit 8) in Head and Neck Squamous Cell Carcinoma (HNSCC) remains elusive. In this study, we found EMC8 is significantly upregulated in HNSCC tissues compared to adjacent normal tissues, at both mRNA and protein levels. Kaplan-Meier survival analyses demonstrated that high EMC8 expression is associated with poorer overall survival, disease-specific survival, and progression-free interval in HNSCC patients. Further exploration into the tumor microenvironment showed that EMC8 expression negatively correlates with the infiltration of multiple immune cells, particularly CD8 + T cells, which was validated in clinical samples where high EMC8 expression corresponded to reduced CD8 + T cell infiltration. Additionally, single-cell RNA sequencing data indicated that EMC8 expression is positively associated with dedifferentiation, hypoxia, and stemness properties of HNSCC cells. Collectively, EMC8 upregulation in HNSCC correlates with poor prognosis, reduced CD8 + T cell infiltration, and aggressive phenotypes, positioning it as a potential prognostic marker with mechanistic links to immune evasion and malignancy warranting deeper exploration.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"276 ","pages":"Article 156255"},"PeriodicalIF":3.2,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145242391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1016/j.prp.2025.156256
Laura Gabriela Sánchez-Lozada , Fernando García-Arroyo , Guillermo Gonzaga-Sánchez , Omar Emiliano Aparicio-Trejo , Belén Cuevas , Marlene Reyes-Leo , Bernardo Rodríguez-Iturbe , Richard J. Johnson
Identifying potential mechanisms by which hyperuricemia might cause kidney diseases is important, as it may help identify new therapies. Nicotinamide adenine dinucleotide (NAD+) is a coenzyme involved in hundreds of metabolic reactions, including bioenergetics, DNA repair, and gene expression. Hyperuricemia (HU) is a common metabolic disorder associated with the development of chronic kidney disease (CKD), beyond its well-established links to gout and kidney stones. Here, we review the complex relationship between NAD+ levels, HU, and renal damage. Uric acid (UA) crystal deposition induces a local inflammatory response linked to Toll-like receptor and inflammasome activation, while soluble UA drives mitochondrial and endothelial dysfunction, activation of the renin-angiotensin system, inflammation, and epithelial and endothelial-to-mesenchymal transition. Here we discuss how oxidative stress, mitochondrial dysfunction, and inflammation from HU can indirectly deplete intracellular NAD+ by increasing the activity of NAD+-consuming enzymes. Given NAD+´s critical role in kidney health, therapeutically increasing NAD+ levels through precursor supplementation (e.g., nicotinamide, nicotinamide riboside, nicotinamide mononucleotide) or inhibiting NAD+ consuming enzymes shows promise for preventing or treating HU-associated kidney damage. We recommend clinical trials to determine if increasing NAD+ levels can improve the management of HU-induced kidney disease.
{"title":"The interplay of NAD+, hyperuricemia, and renal damage: A scientific review","authors":"Laura Gabriela Sánchez-Lozada , Fernando García-Arroyo , Guillermo Gonzaga-Sánchez , Omar Emiliano Aparicio-Trejo , Belén Cuevas , Marlene Reyes-Leo , Bernardo Rodríguez-Iturbe , Richard J. Johnson","doi":"10.1016/j.prp.2025.156256","DOIUrl":"10.1016/j.prp.2025.156256","url":null,"abstract":"<div><div>Identifying potential mechanisms by which hyperuricemia might cause kidney diseases is important, as it may help identify new therapies. Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) is a coenzyme involved in hundreds of metabolic reactions, including bioenergetics, DNA repair, and gene expression. Hyperuricemia (HU) is a common metabolic disorder associated with the development of chronic kidney disease (CKD), beyond its well-established links to gout and kidney stones. Here, we review the complex relationship between NAD<sup>+</sup> levels, HU, and renal damage. Uric acid (UA) crystal deposition induces a local inflammatory response linked to Toll-like receptor and inflammasome activation, while soluble UA drives mitochondrial and endothelial dysfunction, activation of the renin-angiotensin system, inflammation, and epithelial and endothelial-to-mesenchymal transition. Here we discuss how oxidative stress, mitochondrial dysfunction, and inflammation from HU can indirectly deplete intracellular NAD<sup>+</sup> by increasing the activity of NAD<sup>+</sup>-consuming enzymes. Given NAD<sup>+</sup>´s critical role in kidney health, therapeutically increasing NAD<sup>+</sup> levels through precursor supplementation (e.g., nicotinamide, nicotinamide riboside, nicotinamide mononucleotide) or inhibiting NAD<sup>+</sup> consuming enzymes shows promise for preventing or treating HU-associated kidney damage. We recommend clinical trials to determine if increasing NAD<sup>+</sup> levels can improve the management of HU-induced kidney disease.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156256"},"PeriodicalIF":3.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-03DOI: 10.1016/j.prp.2025.156254
Szu-Ni Huang , Yu-Chien Kao , Jen-Chieh Lee , Hsuan-Ying Huang , Chen Chang , Wan-Shan Li , Tsung-Han Hsieh , Mann Hua Nam
Pseudomyogenic hemangioendothelioma (PHE) is a rare vascular tumor of intermediate biologic behavior. It typically occurs in the lower extremities of young adults, and is molecularly characterized by FOSB gene rearrangements, most commonly with SERPINE1 or ACTB fusion partners. Multifocality and local recurrence are common, but distant metastasis is rare. In this retrospective study, we collected 13 cases of PHEs and described their clinicopathologic features and available molecular findings. The patients ranged from 4 to 78 years of age, and had a male predilection (male: female=3.3: 1). The tumors involved the lower extremities (n = 4), upper extremities (n = 4), trunk (n = 3), and most extraordinarily, the heart (n = 2). Most cases showed typical histologic features with eosinophilic plump spindle cells, frequent inflammatory infiltrate, and immunoreactivity to cytokeratin (9/9), ERG (8/8), CD31(5/9), FOSB (7/7), and rarely CD34 (1/6). One exceptional case showed an extensive myxoid stroma and spindle to epithelioid cytomorphology. Molecular findings were available in 4 cases, with SERPINE1::FOSB, ACTB::FOSB, MAPK1IP1L::FOSB, and NPIPA7::NIPBL fusions in one case each. The novel MAPK1IP1L::FOSB and NPIPA7::NIPBL fusions were both detected in cardiac tumors. In total, 4 patients had metastatic diseases, which affected the bones (n = 3), lungs (n = 2), skin (n = 1), brain (n = 1), and lymph nodes (n = 1). Two patients died of diseases, both with pulmonary metastasis at initial presentation. In conclusion, our cohort expands the clinicopathologic spectrum of PHE, with a wide range of age, cases with unusual cardiac locations, novel MAPK1IP1L::FOSB and NPIPA7::NIPBL fusions, and uncommon malignant behavior.
{"title":"Pseudomyogenic hemangioendothelioma: A series of 13 patients, highlighting unusual cardiac locations, novel gene fusions, and malignant behavior","authors":"Szu-Ni Huang , Yu-Chien Kao , Jen-Chieh Lee , Hsuan-Ying Huang , Chen Chang , Wan-Shan Li , Tsung-Han Hsieh , Mann Hua Nam","doi":"10.1016/j.prp.2025.156254","DOIUrl":"10.1016/j.prp.2025.156254","url":null,"abstract":"<div><div>Pseudomyogenic hemangioendothelioma (PHE) is a rare vascular tumor of intermediate biologic behavior. It typically occurs in the lower extremities of young adults, and is molecularly characterized by <em>FOSB</em> gene rearrangements, most commonly with <em>SERPINE1</em> or <em>ACTB</em> fusion partners. Multifocality and local recurrence are common, but distant metastasis is rare. In this retrospective study, we collected 13 cases of PHEs and described their clinicopathologic features and available molecular findings. The patients ranged from 4 to 78 years of age, and had a male predilection (male: female=3.3: 1). The tumors involved the lower extremities (n = 4), upper extremities (n = 4), trunk (n = 3), and most extraordinarily, the heart (n = 2). Most cases showed typical histologic features with eosinophilic plump spindle cells, frequent inflammatory infiltrate, and immunoreactivity to cytokeratin (9/9), ERG (8/8), CD31(5/9), FOSB (7/7), and rarely CD34 (1/6). One exceptional case showed an extensive myxoid stroma and spindle to epithelioid cytomorphology. Molecular findings were available in 4 cases, with <em>SERPINE1</em>::<em>FOSB</em>, <em>ACTB</em>::<em>FOSB</em>, <em>MAPK1IP1L</em>::<em>FOSB,</em> and <em>NPIPA7</em>::<em>NIPBL</em> fusions in one case each. The novel <em>MAPK1IP1L</em>::<em>FOSB and NPIPA7</em>::<em>NIPBL</em> fusions were both detected in cardiac tumors. In total, 4 patients had metastatic diseases, which affected the bones (n = 3), lungs (n = 2), skin (n = 1), brain (n = 1), and lymph nodes (n = 1). Two patients died of diseases, both with pulmonary metastasis at initial presentation. In conclusion, our cohort expands the clinicopathologic spectrum of PHE, with a wide range of age, cases with unusual cardiac locations, novel <em>MAPK1IP1L</em>::<em>FOSB</em> and <em>NPIPA7</em>::<em>NIPBL</em> fusions, and uncommon malignant behavior.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156254"},"PeriodicalIF":3.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-07-29DOI: 10.1016/j.prp.2025.156154
Qiang Zhou, Wei Zhang, Jun Huang, Wenbing Hu
Ferroptosis exerts a remarkable influence on the progression of non-small cell lung cancer (NSCLC). Although the contribution of lipocalin 2 (LCN2) to NSCLC pathogenesis has been demonstrated, further elucidation of the molecular determinants driving LCN2 dysregulation is essential for developing NSCLC interventions. mRNA levels were performed by quantitative polymerase chain reaction (PCR), and protein expression was assessed by immunoblotting and immunohistochemical assays. Reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and Fe2 + levels were measured to analyze cell ferroptosis. The relationship between zinc-finger E-box-binding homeobox 1 (ZEB1) and the LCN2 promoter was verified by chromatin immunoprecipitation (ChIP) and luciferase assays. Our data showed that LCN2 and ZEB1 levels were upregulated in NSCLC. LCN2 depletion reduced the growth, motility, and invasiveness of NSCLC cells, while promoting apoptosis and ferroptosis. LCN2 depletion also inhibited the tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. Mechanistically, ZEB1 enhanced the transcription and expression of LCN2 in NSCLC cells. ZEB1 downregulation diminished HUVEC tube formation, suppressed the growth, motility, and invasiveness of NSCLC cells, and enhanced apoptosis and ferroptosis. Notably, these effects were counteracted by re-expression of LCN2. Additionally, ZEB1 downregulation inhibited the growth of xenograft tumors in vivo. Our study demonstrates the pro-tumorigenic role of the ZEB1/LCN2 cascade in NSCLC by promoting malignant progression and impeding ferroptosis. Such molecular insights may help devise novel candidates for NSCLC treatment.
{"title":"ZEB1-upregulated LCN2 via transcription regulation affects ferroptosis and malignant progression in non-small cell lung cancer.","authors":"Qiang Zhou, Wei Zhang, Jun Huang, Wenbing Hu","doi":"10.1016/j.prp.2025.156154","DOIUrl":"10.1016/j.prp.2025.156154","url":null,"abstract":"<p><p>Ferroptosis exerts a remarkable influence on the progression of non-small cell lung cancer (NSCLC). Although the contribution of lipocalin 2 (LCN2) to NSCLC pathogenesis has been demonstrated, further elucidation of the molecular determinants driving LCN2 dysregulation is essential for developing NSCLC interventions. mRNA levels were performed by quantitative polymerase chain reaction (PCR), and protein expression was assessed by immunoblotting and immunohistochemical assays. Reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and Fe<sup>2 +</sup> levels were measured to analyze cell ferroptosis. The relationship between zinc-finger E-box-binding homeobox 1 (ZEB1) and the LCN2 promoter was verified by chromatin immunoprecipitation (ChIP) and luciferase assays. Our data showed that LCN2 and ZEB1 levels were upregulated in NSCLC. LCN2 depletion reduced the growth, motility, and invasiveness of NSCLC cells, while promoting apoptosis and ferroptosis. LCN2 depletion also inhibited the tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. Mechanistically, ZEB1 enhanced the transcription and expression of LCN2 in NSCLC cells. ZEB1 downregulation diminished HUVEC tube formation, suppressed the growth, motility, and invasiveness of NSCLC cells, and enhanced apoptosis and ferroptosis. Notably, these effects were counteracted by re-expression of LCN2. Additionally, ZEB1 downregulation inhibited the growth of xenograft tumors in vivo. Our study demonstrates the pro-tumorigenic role of the ZEB1/LCN2 cascade in NSCLC by promoting malignant progression and impeding ferroptosis. Such molecular insights may help devise novel candidates for NSCLC treatment.</p>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"274 ","pages":"156154"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objective: Tumor microenvironment composition significantly influences tumor progression. This study aimed to explore the distribution of M2 tumor-associated macrophages (TAMs), reticular fibers (RFs), and collagen fibers (CFs) within the tumor microenvironment of pulmonary sarcomatoid carcinoma (PSC) and assess their clinicopathological significance.
Methods: Formalin-fixed paraffin tissue sections of 127 PSC patients from two medical centers were collected and analyzed by immunohistochemistry and the Gomori method. HALO software was used to analyze the distributions of M2TAMs, RFs, and CFs, and statistically analyzed for clinicopathological significance.
Results: Kaplan-Meier analysis showed that overall survival (OS) was longer in patients with low density of M2TAMs (P = 0.038) and high density of CFs (P = 0.046) and RFs (P = 0.010). Patients classified within the low-risk group, based on the combined factors MR and MC, experienced significantly longer OS than those in the high-risk group. Multivariate analysis identified the densities of M2TAMs, RFs, and CFs, along with MC and MR, as independent prognostic factors for patient OS. Nomogram models 1 and 2, with C-indices of 0.74 and 0.73, respectively, were highly effective in predicting OS. Decision curve analysis demonstrated that the Nomogram model outperformed pTNM staging in predicting medium- and long-term survival.
Conclusion: High densities of M2TAMs and low densities of RFs and CFs are associated with poor prognosis in PSC patients and are independent prognostic factors. The Nomogram model proved was more effective than pTNM staging in predicting medium- and long-term survival, offering a valuable tool for the individualized clinical treatment of PSC patients.
{"title":"A nomogram integrating M2 macrophages and extracellular matrix components outperforms TNM classification in pulmonary sarcomatoid carcinoma prognosis: A two-center retrospective study.","authors":"Chao Ma, Yaoying Li, Chengyou Zheng, Suijing Wang, Yuanqing Zhang, Haibo Wu, Zhengyi Zhou, Jierong Chen, Keming Chen, Xinke Zhang, Yangfan He, Junpeng Lai, Jiewei Chen","doi":"10.1016/j.prp.2025.156161","DOIUrl":"10.1016/j.prp.2025.156161","url":null,"abstract":"<p><strong>Objective: </strong>Tumor microenvironment composition significantly influences tumor progression. This study aimed to explore the distribution of M2 tumor-associated macrophages (TAMs), reticular fibers (RFs), and collagen fibers (CFs) within the tumor microenvironment of pulmonary sarcomatoid carcinoma (PSC) and assess their clinicopathological significance.</p><p><strong>Methods: </strong>Formalin-fixed paraffin tissue sections of 127 PSC patients from two medical centers were collected and analyzed by immunohistochemistry and the Gomori method. HALO software was used to analyze the distributions of M<sub>2</sub>TAMs, RFs, and CFs, and statistically analyzed for clinicopathological significance.</p><p><strong>Results: </strong>Kaplan-Meier analysis showed that overall survival (OS) was longer in patients with low density of M<sub>2</sub>TAMs (P = 0.038) and high density of CFs (P = 0.046) and RFs (P = 0.010). Patients classified within the low-risk group, based on the combined factors MR and MC, experienced significantly longer OS than those in the high-risk group. Multivariate analysis identified the densities of M<sub>2</sub>TAMs, RFs, and CFs, along with MC and MR, as independent prognostic factors for patient OS. Nomogram models 1 and 2, with C-indices of 0.74 and 0.73, respectively, were highly effective in predicting OS. Decision curve analysis demonstrated that the Nomogram model outperformed pTNM staging in predicting medium- and long-term survival.</p><p><strong>Conclusion: </strong>High densities of M<sub>2</sub>TAMs and low densities of RFs and CFs are associated with poor prognosis in PSC patients and are independent prognostic factors. The Nomogram model proved was more effective than pTNM staging in predicting medium- and long-term survival, offering a valuable tool for the individualized clinical treatment of PSC patients.</p>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"274 ","pages":"156161"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01DOI: 10.1016/j.prp.2025.156247
Qin Chen , Jiawei Song , Binbin Zhang, Hongyu Wang, Juan Xu, Xiuqin Li, Xuelian Wang
Objective
To investigate the oncogenic role of DDX27 in colorectal cancer (CRC) and its regulation of EZH2.
Methods
DDX27 expression and prognostic value were analyzed using TCGA. qRT-PCR was performed on 30 paired CRC and adjacent tissues; DDX27 levels in CRC cell lines (HCT116, HT-29, SW480, SW620, HCT-8) were assessed by qRT-PCR and Western blot. Methylation-specific PCR evaluated CpG methylation of the DDX27 promoter and the effect of 5-azacytidine (5-AZ). Functional assays (CCK-8, flow cytometry, wound healing, transwell) examined proliferation, apoptosis, migration and invasion after DDX27 knockdown (si-DDX27). RNA-seq and bioinformatics analyses, together with Western blot assays, were used to identify downstream effectors. Luciferase reporter assays tested EZH2 promoter activity following DDX27 depletion. Rescue experiments overexpressed EZH2 in DDX27-silenced cells. In vivo, HCT116 cells with DDX27 shRNA or control shRNA were implanted in mice and tumor EZH2 was evaluated by IHC.
Results
DDX27 was upregulated in CRC and correlated with poorer prognosis. Promoter hypomethylation was observed and 5-AZ increased DDX27 expression. DDX27 knockdown inhibited proliferation, migration and invasion and increased apoptosis. Silencing DDX27 reduced EZH2 protein and significantly lowered EZH2 promoter luciferase activity. EZH2 overexpression partially rescued the anti-tumor effects of DDX27 silencing. In vivo DDX27 depletion suppressed tumor growth and reduced EZH2 expression.
Conclusions
DDX27 promotes CRC progression partly via transcriptional upregulation of EZH2; promoter hypomethylation contributes to DDX27 overexpression. Targeting the DDX27-EZH2 axis may be therapeutically valuable.
{"title":"DNA methylation-regulated DDX27 promotes colorectal cancer progression through EZH2","authors":"Qin Chen , Jiawei Song , Binbin Zhang, Hongyu Wang, Juan Xu, Xiuqin Li, Xuelian Wang","doi":"10.1016/j.prp.2025.156247","DOIUrl":"10.1016/j.prp.2025.156247","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the oncogenic role of DDX27 in colorectal cancer (CRC) and its regulation of EZH2.</div></div><div><h3>Methods</h3><div>DDX27 expression and prognostic value were analyzed using TCGA. qRT-PCR was performed on 30 paired CRC and adjacent tissues; DDX27 levels in CRC cell lines (HCT116, HT-29, SW480, SW620, HCT-8) were assessed by qRT-PCR and Western blot. Methylation-specific PCR evaluated CpG methylation of the DDX27 promoter and the effect of 5-azacytidine (5-AZ). Functional assays (CCK-8, flow cytometry, wound healing, transwell) examined proliferation, apoptosis, migration and invasion after DDX27 knockdown (si-DDX27). RNA-seq and bioinformatics analyses, together with Western blot assays, were used to identify downstream effectors. Luciferase reporter assays tested EZH2 promoter activity following DDX27 depletion. Rescue experiments overexpressed EZH2 in DDX27-silenced cells. <em>In vivo</em>, HCT116 cells with DDX27 shRNA or control shRNA were implanted in mice and tumor EZH2 was evaluated by IHC.</div></div><div><h3>Results</h3><div>DDX27 was upregulated in CRC and correlated with poorer prognosis. Promoter hypomethylation was observed and 5-AZ increased DDX27 expression. DDX27 knockdown inhibited proliferation, migration and invasion and increased apoptosis. Silencing DDX27 reduced EZH2 protein and significantly lowered EZH2 promoter luciferase activity. EZH2 overexpression partially rescued the anti-tumor effects of DDX27 silencing. <em>In vivo</em> DDX27 depletion suppressed tumor growth and reduced EZH2 expression.</div></div><div><h3>Conclusions</h3><div>DDX27 promotes CRC progression partly via transcriptional upregulation of EZH2; promoter hypomethylation contributes to DDX27 overexpression. Targeting the DDX27-EZH2 axis may be therapeutically valuable.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156247"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: The application of general-purpose large language models (LLMs) in cytopathology remains largely unexplored. This study aims to evaluate the accuracy and consistency of a custom version of ChatGPT-4 (GPT), ChatGPT o3, and Gemini 2.5 Pro as diagnostic support tools for cervical cytology.
Materials and methods: A total of 200 Papanicolaou-stained cervical cytology images were acquired at 40x magnification, each measuring 384 × 384 pixels. These images consisted of 100 cases classified as negative for intraepithelial lesion or malignancy (NILM) and 100 cases across various abnormal categories: 20 low-grade squamous intraepithelial lesion (LSIL), 20 high-grade squamous intraepithelial lesion (HSIL), 20 squamous cell carcinoma (SCC), 20 adenocarcinoma in situ (AIS), and 20 adenocarcinoma (ADC). Diagnostic accuracy and consistency were evaluated by submitting each image to a GPT, ChatGPT o3, and Gemini 2.5 Pro 5-10 times.
Results: When distinguishing normal from abnormal cytology, LLMs showed mean sensitivity between 85.4 % and 100 %, and specificity between 67.2 % and 92.7 %. ChatGPT o3 was more accurate in identifying NILM (mean 89.2 % vs. 67.2 %) but less accurate in detecting LSIL (34 % vs. 85 %), HSIL (6 % vs. 63 %), and ADC (28 % vs. 91 %). Chain-of-thought prompting and submitting multiple images of the same diagnosis to ChatGPT o3 and Gemini 2.5 Pro did not significantly improve accuracy. Both models also performed poorly in identifying cervicovaginal infections.
Conclusions: ChatGPT o3 and Gemini 2.5 Pro demonstrated complementary strengths in cervical cytology. Due to their low accuracy and inconsistency in abnormal cytology, general-purpose LLMs are not recommended as diagnostic support tools in cervical cytology.
{"title":"Evaluation of general-purpose large language models as diagnostic support tools in cervical cytology.","authors":"Thiyaphat Laohawetwanit, Sompon Apornvirat, Aleksandra Asaturova, Hua Li, Kris Lami, Andrey Bychkov","doi":"10.1016/j.prp.2025.156159","DOIUrl":"10.1016/j.prp.2025.156159","url":null,"abstract":"<p><strong>Introduction: </strong>The application of general-purpose large language models (LLMs) in cytopathology remains largely unexplored. This study aims to evaluate the accuracy and consistency of a custom version of ChatGPT-4 (GPT), ChatGPT o3, and Gemini 2.5 Pro as diagnostic support tools for cervical cytology.</p><p><strong>Materials and methods: </strong>A total of 200 Papanicolaou-stained cervical cytology images were acquired at 40x magnification, each measuring 384 × 384 pixels. These images consisted of 100 cases classified as negative for intraepithelial lesion or malignancy (NILM) and 100 cases across various abnormal categories: 20 low-grade squamous intraepithelial lesion (LSIL), 20 high-grade squamous intraepithelial lesion (HSIL), 20 squamous cell carcinoma (SCC), 20 adenocarcinoma in situ (AIS), and 20 adenocarcinoma (ADC). Diagnostic accuracy and consistency were evaluated by submitting each image to a GPT, ChatGPT o3, and Gemini 2.5 Pro 5-10 times.</p><p><strong>Results: </strong>When distinguishing normal from abnormal cytology, LLMs showed mean sensitivity between 85.4 % and 100 %, and specificity between 67.2 % and 92.7 %. ChatGPT o3 was more accurate in identifying NILM (mean 89.2 % vs. 67.2 %) but less accurate in detecting LSIL (34 % vs. 85 %), HSIL (6 % vs. 63 %), and ADC (28 % vs. 91 %). Chain-of-thought prompting and submitting multiple images of the same diagnosis to ChatGPT o3 and Gemini 2.5 Pro did not significantly improve accuracy. Both models also performed poorly in identifying cervicovaginal infections.</p><p><strong>Conclusions: </strong>ChatGPT o3 and Gemini 2.5 Pro demonstrated complementary strengths in cervical cytology. Due to their low accuracy and inconsistency in abnormal cytology, general-purpose LLMs are not recommended as diagnostic support tools in cervical cytology.</p>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"274 ","pages":"156159"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: To evaluate the clinical, pathological, and prognostic significance of HER2-low and HER2-ultralow expression in breast cancer.
Methods: In this retrospective study, 171 HER2-negative breast cancer cases were reclassified by immunohistochemistry as HER2-low, HER2-ultralow, or HER2 IHC 0. Clinicopathological variables, Ki-67 index, hormone receptor (HR) status, and treatment data were analyzed. Welch's ANOVA, Kaplan-Meier survival with a 60-month landmark, and Cox regression were applied.
Results: The cohort included 49.1 % HER2-low, 27.5 % HER2-ultralow, and 23.4 % HER2 IHC 0 cases. No significant differences were found in clinical stage, histologic grade, or treatment distribution. Ki-67 index was lower in HER2 IHC 0 tumors (p = 0.047). Overall survival (OS) differed significantly: HER2-ultralow patients had the best outcomes (median OS: 47.5 months), followed by HER2 IHC 0 (37.5) and HER2-low (33.0) (log-rank p < 0.05). In multivariable Cox analysis, HER2-low status was independently associated with worse OS versus HER2-ultralow (HR = 1.86; p = 0.006), while HER2 IHC 0 showed no significant difference (HR = 1.42; p = 0.212). Higher Ki-67 and negative ER status were also linked to worse prognosis. Subgroup analysis revealed the poorest outcomes in HER2-low/HR-negative tumors.
Conclusion: HER2-ultralow tumors were associated with better survival than HER2-low, suggesting clinical relevance in further subclassifying HER2-negative breast cancers. Although the retrospective design and minor proportional hazard violations warrant caution, these findings may guide treatment for more individualized approaches. Future multicenter studies, supported by molecular profiling and AI-assisted HER2 scoring, are essential to validate these findings and improve reproducibility in low-level HER2 assessment.
{"title":"Refining HER2-Negative breast cancer: distinct survival profiles of HER2-Low and HER2-Ultralow tumors.","authors":"Dido Eliphas Leão de Alencar, Giuliano Rizzotto Guimarães, Adriana Vial Roehe","doi":"10.1016/j.prp.2025.156140","DOIUrl":"10.1016/j.prp.2025.156140","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the clinical, pathological, and prognostic significance of HER2-low and HER2-ultralow expression in breast cancer.</p><p><strong>Methods: </strong>In this retrospective study, 171 HER2-negative breast cancer cases were reclassified by immunohistochemistry as HER2-low, HER2-ultralow, or HER2 IHC 0. Clinicopathological variables, Ki-67 index, hormone receptor (HR) status, and treatment data were analyzed. Welch's ANOVA, Kaplan-Meier survival with a 60-month landmark, and Cox regression were applied.</p><p><strong>Results: </strong>The cohort included 49.1 % HER2-low, 27.5 % HER2-ultralow, and 23.4 % HER2 IHC 0 cases. No significant differences were found in clinical stage, histologic grade, or treatment distribution. Ki-67 index was lower in HER2 IHC 0 tumors (p = 0.047). Overall survival (OS) differed significantly: HER2-ultralow patients had the best outcomes (median OS: 47.5 months), followed by HER2 IHC 0 (37.5) and HER2-low (33.0) (log-rank p < 0.05). In multivariable Cox analysis, HER2-low status was independently associated with worse OS versus HER2-ultralow (HR = 1.86; p = 0.006), while HER2 IHC 0 showed no significant difference (HR = 1.42; p = 0.212). Higher Ki-67 and negative ER status were also linked to worse prognosis. Subgroup analysis revealed the poorest outcomes in HER2-low/HR-negative tumors.</p><p><strong>Conclusion: </strong>HER2-ultralow tumors were associated with better survival than HER2-low, suggesting clinical relevance in further subclassifying HER2-negative breast cancers. Although the retrospective design and minor proportional hazard violations warrant caution, these findings may guide treatment for more individualized approaches. Future multicenter studies, supported by molecular profiling and AI-assisted HER2 scoring, are essential to validate these findings and improve reproducibility in low-level HER2 assessment.</p>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"274 ","pages":"156140"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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