Pub Date : 2026-02-01Epub Date: 2025-12-05DOI: 10.1016/j.prp.2025.156324
Chenxi Xiang , Shaoqi Li , Jia Liu , Qianqian Yin , Dongshen Ma , Hui Liu
Plasmacytoid dendritic cell (pDC) accumulations are frequently observed in association with myeloid neoplasms in the bone marrow. We report a case diagnosed as acute myeloid leukemia (AML) with pDC differentiation, which first presented as skin lesions and lymphadenopathies. The skin biopsy revealed pDC-like cells infiltrating the dermal layer. The architecture of the cervical lymph node remained largely preserved, but it was infiltrated by monotonous, atypical cells with a pDC-like immunophenotype in the interfollicular areas. Flow cytometry analysis of the lymph node tissue confirmed the heterogeneity and pDC-like immunophenotype of the tumor cells. Furthermore, a bone marrow biopsy confirmed the presence of underlying AML. DNA sequencing demonstrated that the tumor cells in both the tumor cells in the lymph node and skin biopsy shared the identical genetic abberations as in the bone marrow. Based on these findings, a diagnosis of AML with pDC differentiation was established.
{"title":"Acute myeloid leukemia with plasmacytoid dendritic cell differentiation initially presenting as skin lesions: A case report","authors":"Chenxi Xiang , Shaoqi Li , Jia Liu , Qianqian Yin , Dongshen Ma , Hui Liu","doi":"10.1016/j.prp.2025.156324","DOIUrl":"10.1016/j.prp.2025.156324","url":null,"abstract":"<div><div>Plasmacytoid dendritic cell (pDC) accumulations are frequently observed in association with myeloid neoplasms in the bone marrow. We report a case diagnosed as acute myeloid leukemia (AML) with pDC differentiation, which first presented as skin lesions and lymphadenopathies. The skin biopsy revealed pDC-like cells infiltrating the dermal layer. The architecture of the cervical lymph node remained largely preserved, but it was infiltrated by monotonous, atypical cells with a pDC-like immunophenotype in the interfollicular areas. Flow cytometry analysis of the lymph node tissue confirmed the heterogeneity and pDC-like immunophenotype of the tumor cells. Furthermore, a bone marrow biopsy confirmed the presence of underlying AML. DNA sequencing demonstrated that the tumor cells in both the tumor cells in the lymph node and skin biopsy shared the identical genetic abberations as in the bone marrow. Based on these findings, a diagnosis of AML with pDC differentiation was established.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156324"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145725153","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 : 2026-02-01Epub Date: 2025-12-16DOI: 10.1016/j.prp.2025.156334
Shangomitra Bhattacharjee, Mahaboobkhan Rasool
Tissue inhibitors of matrix metalloproteinase 1 (TIMP-1) have recently attracted significant attention owing to their newly discovered cytokine function. These findings prompted a reevaluation of TIMP-1's role as an inhibitor of matrix metalloproteinase. Elevated TIMP-1 levels have been observed in various autoimmune conditions, influencing disease outcomes in multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis. Furthermore, TIMP-1 affects context-dependent metabolic profiles, enhances glycolytic turnover in monocytes, and is associated with ferroptosis in patients with rheumatoid arthritis. TIMP-1 also supports MHC-I expression and CD8 + T-cell activation, indicating a more active role in autoimmune conditions. Considering the expanding body of knowledge regarding TIMP-1 and its significant role in modifying metabolic profiles and disease outcomes, we carefully reviewed the contrasting functions of TIMP-1. Additionally, we summarize the upstream activators and signaling pathways involved in TIMP-1 activation and its reciprocal effects. Although TIMP-1 expression is linked to diverse disease outcomes, it is advisable to adopt a more nuanced approach to utilizing TIMP-1 depending on the specific disease context. This review proposes various strategies for targeting TIMP-1 as a therapeutic intervention to modulate the outcomes of autoimmune disorders.
{"title":"Harnessing the therapeutic potential of TIMP-1 in autoimmune inflammation: A prospective insight","authors":"Shangomitra Bhattacharjee, Mahaboobkhan Rasool","doi":"10.1016/j.prp.2025.156334","DOIUrl":"10.1016/j.prp.2025.156334","url":null,"abstract":"<div><div>Tissue inhibitors of matrix metalloproteinase 1 (TIMP-1) have recently attracted significant attention owing to their newly discovered cytokine function. These findings prompted a reevaluation of TIMP-1's role as an inhibitor of matrix metalloproteinase. Elevated TIMP-1 levels have been observed in various autoimmune conditions, influencing disease outcomes in multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis. Furthermore, TIMP-1 affects context-dependent metabolic profiles, enhances glycolytic turnover in monocytes, and is associated with ferroptosis in patients with rheumatoid arthritis. TIMP-1 also supports MHC-I expression and CD8 + T-cell activation, indicating a more active role in autoimmune conditions. Considering the expanding body of knowledge regarding TIMP-1 and its significant role in modifying metabolic profiles and disease outcomes, we carefully reviewed the contrasting functions of TIMP-1. Additionally, we summarize the upstream activators and signaling pathways involved in TIMP-1 activation and its reciprocal effects. Although TIMP-1 expression is linked to diverse disease outcomes, it is advisable to adopt a more nuanced approach to utilizing TIMP-1 depending on the specific disease context. This review proposes various strategies for targeting TIMP-1 as a therapeutic intervention to modulate the outcomes of autoimmune disorders.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156334"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775383","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 : 2026-02-01Epub Date: 2025-11-24DOI: 10.1016/j.prp.2025.156305
Fan Yang , Chi Peng , Sisi Yang , Xiuwu Bian , Xiaohong Yao
Glioblastoma (GBM), a highly vascularized and aggressive primary brain tumor, presents unresolved questions regarding the functional significance of angiogenesis-related genes (ARGs) in disease progression. To systematically investigate this, we employed univariate Cox regression followed by LASSO regression analysis to identify prognosis-associated ARGs. These candidates were subsequently evaluated using six machine learning-derived survival prediction algorithms, with model interpretability achieved through SHapley Additive exPlanations (SHAP) analysis. Our studies revealed that six hub ARGs (BMP2, FSCN1, NET1, AEBP1, SEMA3G, and RAB37) were identified and incorporated into a novel risk stratification model (high and low risk groups). High-risk patients demonstrated significantly poorer overall survival in the CGGA-GBM, GSE43378, and GSE7696 cohorts. Moreover, the high-risk group exhibited an immunosuppressive tumor microenvironment profile (e.g., elevated Treg infiltration, P < 0.0001), increased extracellular matrix stiffness (via mechanosensing markers) and differential drug sensitivity (OncoPredict analysis). Immunofluorescence confirmed co-localization of the hub protein FSCN1 with vascular (CD31⁺), stromal (α-SMA⁺), and mesenchymal (Vimentin⁺) compartments, suggesting its multifunctional role in GBM pathobiology. In summary, our research established the ARG-derived prognostic signature validated across independent GBM cohorts and revealed concomitant immune and mechanical niche dysregulation in high-risk patients. The rationale for combined angiogenesis/stroma/immune modulation strategies was provided, with FSCN1 proposed as the potential therapeutic target.
{"title":"Deciphering the role of angiogenesis in glioblastoma: Integrative insights from transcriptomic profiling, single-cell sequencing and interpretable machine learning approaches","authors":"Fan Yang , Chi Peng , Sisi Yang , Xiuwu Bian , Xiaohong Yao","doi":"10.1016/j.prp.2025.156305","DOIUrl":"10.1016/j.prp.2025.156305","url":null,"abstract":"<div><div>Glioblastoma (GBM), a highly vascularized and aggressive primary brain tumor, presents unresolved questions regarding the functional significance of angiogenesis-related genes (ARGs) in disease progression. To systematically investigate this, we employed univariate Cox regression followed by LASSO regression analysis to identify prognosis-associated ARGs. These candidates were subsequently evaluated using six machine learning-derived survival prediction algorithms, with model interpretability achieved through SHapley Additive exPlanations (SHAP) analysis. Our studies revealed that six hub ARGs (BMP2, FSCN1, NET1, AEBP1, SEMA3G, and RAB37) were identified and incorporated into a novel risk stratification model (high and low risk groups). High-risk patients demonstrated significantly poorer overall survival in the CGGA-GBM, GSE43378, and GSE7696 cohorts. Moreover, the high-risk group exhibited an immunosuppressive tumor microenvironment profile (e.g., elevated Treg infiltration, <em>P</em> < 0.0001), increased extracellular matrix stiffness (via mechanosensing markers) and differential drug sensitivity (OncoPredict analysis). Immunofluorescence confirmed co-localization of the hub protein FSCN1 with vascular (CD31⁺), stromal (α-SMA⁺), and mesenchymal (Vimentin⁺) compartments, suggesting its multifunctional role in GBM pathobiology. In summary, our research established the ARG-derived prognostic signature validated across independent GBM cohorts and revealed concomitant immune and mechanical niche dysregulation in high-risk patients. The rationale for combined angiogenesis/stroma/immune modulation strategies was provided, with FSCN1 proposed as the potential therapeutic target.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156305"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743740","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}
Lactic acidosis is a characteristic feature of solid hypoxic cancerous tumors, those that develop in the breast, colon, and prostate tissue. Even though extreme lactic acidosis is damaging to healthy cells, malignant tumors actually benefit from it in several different ways. Lactic acidosis in TME (TME) imparts resistance to chemotherapy and helps them from immune invasion. Lactic acidosis further benefits the tumor cells by inducing the formation of new blood vessels. Acidic tumour microenvironment (TME) provides very favourable pH conditions for activation of proteolytic enzymes like Matrix metalloproteinase (MMP-2/9), which helps the tumor cells invade into the nearby organs. Because aggressive hypoxic cancer cells have a high chance of metastasising to other organs, it is difficult to manage a tumor at this stage with chemotherapy. Stopping hypoxia-induced Lactate dehydrogenase (LDH) from working can prevent cancers from behaving aggressively. Restraining lactate circulation in the TME by inhibiting LDH and its transporters i.e Monocarboxylate transporters (MCT-1/2) would be a promising therapeutic strategy to prevent metastatic transformation of solid hypoxic tumors. Moreover, nanotechnology can be implicated in various ways to selectively kill the cancer cells. Whereas in some cancers, chemotherapeutic agents fail to activate, pH-sensitive nanoparticles can be designed to target such cancer cells. In the current review, we have highlighted the role and mechanisms of lactic acidosis to transform the benign tumours into more aggressive metastatic tumors. This review also offers fresh perspectives on the variety of LDH and MCT inhibitors currently undergoing clinical trials to act in the acidic TME.
{"title":"LDH-driven lactic acidosis in hypoxic solid tumors: Mechanisms of metastatic transformation and therapeutic opportunities","authors":"Priyanshu Kumar , Saumya Rastogi , Mandeep Kumar Arora , Lakhveer Singh","doi":"10.1016/j.prp.2025.156342","DOIUrl":"10.1016/j.prp.2025.156342","url":null,"abstract":"<div><div>Lactic acidosis is a characteristic feature of solid hypoxic cancerous tumors, those that develop in the breast, colon, and prostate tissue. Even though extreme lactic acidosis is damaging to healthy cells, malignant tumors actually benefit from it in several different ways. Lactic acidosis in TME (TME) imparts resistance to chemotherapy and helps them from immune invasion. Lactic acidosis further benefits the tumor cells by inducing the formation of new blood vessels. Acidic tumour microenvironment (TME) provides very favourable pH conditions for activation of proteolytic enzymes like Matrix metalloproteinase (MMP-2/9), which helps the tumor cells invade into the nearby organs. Because aggressive hypoxic cancer cells have a high chance of metastasising to other organs, it is difficult to manage a tumor at this stage with chemotherapy. Stopping hypoxia-induced Lactate dehydrogenase (LDH) from working can prevent cancers from behaving aggressively. Restraining lactate circulation in the TME by inhibiting LDH and its transporters i.e Monocarboxylate transporters (MCT-1/2) would be a promising therapeutic strategy to prevent metastatic transformation of solid hypoxic tumors. Moreover, nanotechnology can be implicated in various ways to selectively kill the cancer cells. Whereas in some cancers, chemotherapeutic agents fail to activate, pH-sensitive nanoparticles can be designed to target such cancer cells. In the current review, we have highlighted the role and mechanisms of lactic acidosis to transform the benign tumours into more aggressive metastatic tumors. This review also offers fresh perspectives on the variety of LDH and MCT inhibitors currently undergoing clinical trials to act in the acidic TME.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156342"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840766","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 : 2026-02-01Epub Date: 2025-12-29DOI: 10.1016/j.prp.2025.156347
Mokhtar Rejili , Farid Hashemi
Polyploid Giant Cancer Cell (PGCCs) have emerged as pivotal players in cancer biology, contributing to tumor heterogeneity, recurrence, metastasis, and resistance to conventional therapies. Characterized by their enlarged size, aberrant nuclear morphology, and stem-like properties, PGCCs arise in response to environmental stressors such as chemotherapy, radiation, and hypoxia. These cells enter a dormant state, evade treatment, and later become reactivated to generate tumor-repopulating progeny through depolyploidization and asymmetric division (neosis). Daughter cells derived from PGCCs exhibit enhanced invasive capabilities, epithelial-to-mesenchymal transition (EMT), and metabolic adaptability, rendering PGCCs formidable obstacles in cancer management. Their unique biology involves complex molecular mechanisms including endoreplication, cell fusion, and autophagy, which facilitate survival and proliferation under stress conditions. Elucidating PGCC formation and behavior opens new avenues for targeted therapeutic strategies, encompassing immunomodulation, metabolic interference, and differentiation-based approaches. This paradigm shift in cancer research underscores the urgency for innovative diagnostic tools and personalized treatment modalities to effectively counter PGCC-driven malignancies.
多倍体巨癌细胞（Polyploid Giant Cancer Cell, PGCCs）在癌症生物学中扮演着关键角色，对肿瘤的异质性、复发、转移和对常规治疗的耐药性起着重要作用。pgcc的特点是体积增大、核形态异常和茎样性质，是对环境应激因素（如化疗、放疗和缺氧）的反应。这些细胞进入休眠状态，逃避治疗，然后重新激活，通过去多倍体和不对称分裂（新生）产生肿瘤再生的后代。pgcc衍生的子细胞表现出增强的侵袭能力、上皮-间质转化（EMT）和代谢适应性，使pgcc在癌症治疗中成为巨大的障碍。它们独特的生物学涉及复杂的分子机制，包括内复制、细胞融合和自噬，这些机制促进了应激条件下的生存和增殖。阐明PGCC的形成和行为为靶向治疗策略开辟了新的途径，包括免疫调节、代谢干扰和基于分化的方法。癌症研究的这种范式转变强调了创新诊断工具和个性化治疗方式的紧迫性，以有效对抗pgcc驱动的恶性肿瘤。
{"title":"Unveiling the role of PGCCs in tumor recurrence and therapeutic resistance: Hidden architects of cancer’s comeback","authors":"Mokhtar Rejili , Farid Hashemi","doi":"10.1016/j.prp.2025.156347","DOIUrl":"10.1016/j.prp.2025.156347","url":null,"abstract":"<div><div>Polyploid Giant Cancer Cell (PGCCs) have emerged as pivotal players in cancer biology, contributing to tumor heterogeneity, recurrence, metastasis, and resistance to conventional therapies. Characterized by their enlarged size, aberrant nuclear morphology, and stem-like properties, PGCCs arise in response to environmental stressors such as chemotherapy, radiation, and hypoxia. These cells enter a dormant state, evade treatment, and later become reactivated to generate tumor-repopulating progeny through depolyploidization and asymmetric division (neosis). Daughter cells derived from PGCCs exhibit enhanced invasive capabilities, epithelial-to-mesenchymal transition (EMT), and metabolic adaptability, rendering PGCCs formidable obstacles in cancer management. Their unique biology involves complex molecular mechanisms including endoreplication, cell fusion, and autophagy, which facilitate survival and proliferation under stress conditions. Elucidating PGCC formation and behavior opens new avenues for targeted therapeutic strategies, encompassing immunomodulation, metabolic interference, and differentiation-based approaches. This paradigm shift in cancer research underscores the urgency for innovative diagnostic tools and personalized treatment modalities to effectively counter PGCC-driven malignancies.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156347"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884321","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 : 2026-02-01Epub Date: 2025-12-05DOI: 10.1016/j.prp.2025.156325
Nannan Luan , Feng Jin , Zhenhua Hu , Miao Lu , Jian Gao , Liancheng Zhu
Background
Lactylation is acknowledged as a regulator of numerous biological processes related to cancer. Research on the ability of lactylation-related genes (LacRGs) to predict prognosis and immunotherapeutic response in ovarian cancer (OC) patients is limited.
Methods
Consensus clustering was utilized to identify prognostic differentially expressed genes (DEGs) across clusters. A consensus lactylation-related gene signature (LRGS) was established from TCGA-OC and four independent GSE datasets through a machine learning-based integrative approach.
Results
LRGS demonstrates consistent and robust performance as an independent risk factor for overall survival. Furthermore, while the low-LRGS group is more likely to exhibit the "hot tumor" phenotype, it also shows a more favorable prognosis and enhanced responsiveness to immunotherapy. Patients exhibiting a high LRGS demonstrated a reduced probability of deriving benefit from immunotherapy and faced a poor prognosis. The oncogenic role of the risk gene RPS6KA2 was preliminarily validated.
Conclusions
An in-depth analysis of the LacRGs data may yield valuable insights and enhance the molecular classification of OC. The identification of LRGS serves as a crucial factor in the early prognosis of patients and the selection of potential candidates for immunotherapy. The findings have significant implications for individual patients with OC.
{"title":"Development of a lactylation-related molecular classification and machine learning-based gene signature to predict survival, response to immunotherapy for ovarian cancer","authors":"Nannan Luan , Feng Jin , Zhenhua Hu , Miao Lu , Jian Gao , Liancheng Zhu","doi":"10.1016/j.prp.2025.156325","DOIUrl":"10.1016/j.prp.2025.156325","url":null,"abstract":"<div><h3>Background</h3><div>Lactylation is acknowledged as a regulator of numerous biological processes related to cancer. Research on the ability of lactylation-related genes (LacRGs) to predict prognosis and immunotherapeutic response in ovarian cancer (OC) patients is limited.</div></div><div><h3>Methods</h3><div>Consensus clustering was utilized to identify prognostic differentially expressed genes (DEGs) across clusters. A consensus lactylation-related gene signature (LRGS) was established from TCGA-OC and four independent GSE datasets through a machine learning-based integrative approach.</div></div><div><h3>Results</h3><div>LRGS demonstrates consistent and robust performance as an independent risk factor for overall survival. Furthermore, while the low-LRGS group is more likely to exhibit the \"hot tumor\" phenotype, it also shows a more favorable prognosis and enhanced responsiveness to immunotherapy. Patients exhibiting a high LRGS demonstrated a reduced probability of deriving benefit from immunotherapy and faced a poor prognosis. The oncogenic role of the risk gene RPS6KA2 was preliminarily validated.</div></div><div><h3>Conclusions</h3><div>An in-depth analysis of the LacRGs data may yield valuable insights and enhance the molecular classification of OC. The identification of LRGS serves as a crucial factor in the early prognosis of patients and the selection of potential candidates for immunotherapy. The findings have significant implications for individual patients with OC.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156325"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145725127","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 : 2026-02-01Epub Date: 2025-12-29DOI: 10.1016/j.prp.2025.156346
Yizhang Wang , Min Lin , Meifang Zeng
NEK8 is a kinase involved in diverse cellular processes. Accumulating evidence has demonstrated that NEK8 contributes to the development of colorectal cancer (CRC). However, the regulation of its protein stability is poorly understood. Deubiquitinases, such as USP51, can keep protein levels stable by cleaving ubiquitin chains off. In this study, GEO analysis demonstrated elevated expression of USP51, while NEK8 mRNA levels showed no significant difference between CRC tissues and adjacent normal tissues, indicating post-transcriptional regulation. Immunohistochemistry showed a high expression of both NEK8 and USP51 proteins in cancer tissues and a positive correlation between them. Tissue microarray assay verified that NEK8 is an independent risk factor for CRC. In vitro functional experiments confirmed that NEK8 and USP51 promoted proliferation, colony formation, invasion, and migration of CRC, and a subcutaneous tumor formation assay further verified the oncogenic function of NEK8. Co-immunoprecipitation, co-immunofluorescence, ubiquitination assays, and functional rescue experiments proved that USP51 directly interacted with NEK8 and lowered the ubiquitination level of NEK8. Functional enrichment assays demonstrated that NEK8 modulates the WNT/β-catenin pathway. The knockdown of NEK8 resulted in decreased β-catenin protein levels. Taken together, our study reveals that the USP51-NEK8 axis promotes progression of CRC via the β-catenin pathway and could be a potential target for the treatment of CRC.
{"title":"NEK8 stabilization via USP51-mediated deubiquitination promotes colorectal cancer progression","authors":"Yizhang Wang , Min Lin , Meifang Zeng","doi":"10.1016/j.prp.2025.156346","DOIUrl":"10.1016/j.prp.2025.156346","url":null,"abstract":"<div><div>NEK8 is a kinase involved in diverse cellular processes. Accumulating evidence has demonstrated that NEK8 contributes to the development of colorectal cancer (CRC). However, the regulation of its protein stability is poorly understood. Deubiquitinases, such as USP51, can keep protein levels stable by cleaving ubiquitin chains off. In this study, GEO analysis demonstrated elevated expression of USP51, while NEK8 mRNA levels showed no significant difference between CRC tissues and adjacent normal tissues, indicating post-transcriptional regulation. Immunohistochemistry showed a high expression of both NEK8 and USP51 proteins in cancer tissues and a positive correlation between them. Tissue microarray assay verified that NEK8 is an independent risk factor for CRC. In vitro functional experiments confirmed that NEK8 and USP51 promoted proliferation, colony formation, invasion, and migration of CRC, and a subcutaneous tumor formation assay further verified the oncogenic function of NEK8. Co-immunoprecipitation, co-immunofluorescence, ubiquitination assays, and functional rescue experiments proved that USP51 directly interacted with NEK8 and lowered the ubiquitination level of NEK8. Functional enrichment assays demonstrated that NEK8 modulates the WNT/β-catenin pathway. The knockdown of NEK8 resulted in decreased β-catenin protein levels. Taken together, our study reveals that the USP51-NEK8 axis promotes progression of CRC via the β-catenin pathway and could be a potential target for the treatment of CRC.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156346"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878792","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 : 2026-02-01Epub Date: 2025-12-05DOI: 10.1016/j.prp.2025.156323
Ameeduzzafar Zafar , Omar Awad Alsaidan , Mohammad Khalid , Md Ali Mujtaba , Ali Alquraini , Mohd Yasir
Non-small cell lung cancer (NSCLC), accounting for nearly 85 % of lung tumors, remains one of the most fatal cancers worldwide. Among the various oncogenic drivers identified in NSCLC, neuregulin-1 (NRG1) gene fusions, though rare, occurring in approximately 0.1–0.3 % of cases, are clinically significant, particularly in invasive mucinous adenocarcinomas. These genomic events trigger abnormal heterodimerization of ERBB2 and ERBB3, stimulating downstream PI3K/AKT and MAPK pathways, which in turn foster uncontrolled growth, metastatic potential, and therapeutic resistance. These genomic events cause ERBB2 and ERBB3 to form abnormal heterodimers that activate downstream PI3K/AKT and MAPK signaling pathways, driving uncontrolled growth, metastasis, and therapeutic resistance. Alongside these mechanisms, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators of cancer-related networks. Although they do not encode proteins, ncRNAs exert influence at transcriptional, post-transcriptional, and epigenetic levels, with the capacity to either suppress or enhance oncogenic processes. This review examines the interplay between ncRNA activity and NRG1 fusion-driven signaling in NSCLC, highlighting their roles in modulating pathways and contributing to drug resistance. Tumor-suppressive miRNAs, such as miR-22 and miR-296–5p, directly target NRG1 or ERBB2/ERBB3 transcripts, thereby weakening aberrant signaling cascades. Conversely, oncogenic ncRNAs like MALAT1 and HOTAIR facilitate epithelial–mesenchymal transition, cell proliferation, and chemoresistance, while circRNAs amplify oncogenic effects by acting as miRNA sponges. Collectively, these regulatory molecules shape the oncogenic landscape of NRG1-rearranged NSCLC and influence therapeutic outcomes. Dysregulated ncRNAs thus hold promise as biomarkers for diagnosis, prognosis, and treatment planning, with therapeutic strategies aimed at restoring tumor-suppressive ncRNAs or inhibiting oncogenic ones offering a potential avenue to overcome resistance in this subset of patients.
{"title":"RNA-based mechanisms underlying oncogenicity and drug resistance in NRG1-rearranged non-small cell lung cancer","authors":"Ameeduzzafar Zafar , Omar Awad Alsaidan , Mohammad Khalid , Md Ali Mujtaba , Ali Alquraini , Mohd Yasir","doi":"10.1016/j.prp.2025.156323","DOIUrl":"10.1016/j.prp.2025.156323","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC), accounting for nearly 85 % of lung tumors, remains one of the most fatal cancers worldwide. Among the various oncogenic drivers identified in NSCLC, neuregulin-1 (NRG1) gene fusions, though rare, occurring in approximately 0.1–0.3 % of cases, are clinically significant, particularly in invasive mucinous adenocarcinomas. These genomic events trigger abnormal heterodimerization of ERBB2 and ERBB3, stimulating downstream PI3K/AKT and MAPK pathways, which in turn foster uncontrolled growth, metastatic potential, and therapeutic resistance. These genomic events cause ERBB2 and ERBB3 to form abnormal heterodimers that activate downstream PI3K/AKT and MAPK signaling pathways, driving uncontrolled growth, metastasis, and therapeutic resistance. Alongside these mechanisms, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators of cancer-related networks. Although they do not encode proteins, ncRNAs exert influence at transcriptional, post-transcriptional, and epigenetic levels, with the capacity to either suppress or enhance oncogenic processes. This review examines the interplay between ncRNA activity and NRG1 fusion-driven signaling in NSCLC, highlighting their roles in modulating pathways and contributing to drug resistance. Tumor-suppressive miRNAs, such as miR-22 and miR-296–5p, directly target NRG1 or ERBB2/ERBB3 transcripts, thereby weakening aberrant signaling cascades. Conversely, oncogenic ncRNAs like MALAT1 and HOTAIR facilitate epithelial–mesenchymal transition, cell proliferation, and chemoresistance, while circRNAs amplify oncogenic effects by acting as miRNA sponges. Collectively, these regulatory molecules shape the oncogenic landscape of NRG1-rearranged NSCLC and influence therapeutic outcomes. Dysregulated ncRNAs thus hold promise as biomarkers for diagnosis, prognosis, and treatment planning, with therapeutic strategies aimed at restoring tumor-suppressive ncRNAs or inhibiting oncogenic ones offering a potential avenue to overcome resistance in this subset of patients.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156323"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743775","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 : 2026-02-01Epub Date: 2025-12-11DOI: 10.1016/j.prp.2025.156331
Shan Wang , Lin Qin , Xiaoli Song , Hejia Yin , Weihong Yang , Robabe Bazesh
Introduction
Fenofibrate (FenoF) has demonstrated potential in regulating glycemia and lipid profiles across various metabolic disorders. However, its effects on the offspring of rats with gestational diabetes mellitus (GDM) have not yet been investigated. This study aims to evaluate the long-term effects of FenoF on glycemic control, lipid metabolism, liver histology, and the expression of key metabolic and inflammatory proteins in the offspring of GDM-exposed rats.
Materials and methods
Pregnant Wistar rats were randomly assigned to four groups (n = 4 per group): Control, GDM, FenoF-treated (100 mg/kg/day, orally), and GDM rats treated with FenoF (GDM + FenoF). Diabetes was induced via a single intraperitoneal injection of streptozotocin (50 mg/kg) on gestational day 12. Six male offspring from each group were randomly selected and maintained on a standard chow diet. The offspring were reared until adulthood (12 weeks of age), at which point plasma glucose levels, lipid profiles, and liver tissue alterations were evaluated through histopathological analysis and Western blotting.
Results
FenoF treatment significantly reduced triglyceride, low-density lipoprotein cholesterol (LDL-C), and glucose levels (P < 0.05), while significantly increasing high-density lipoprotein cholesterol (HDL-C) levels (P < 0.05) in the offspring of GDM rats. FenoF exerted an ameliorative effect in GDM rat offspring, as evidenced by a significant reduction in hepatic TNF-α expression (P < 0.001) and a marked increase in PPARα levels (P < 0.001) compared to the untreated GDM group. Western blot analysis revealed that FenoF treatment significantly downregulated TLR4 and NF-κB expression, indicating attenuation of inflammatory signaling. Moreover, FenoF treatment significantly upregulated AKT1, IRS1, and CPT1A levels, suggesting enhanced insulin signaling and lipid metabolism. Additionally, Histopathological analysis demonstrated that FenoF preserved liver architecture and significantly reduced inflammation and structural abnormalities relative to GDM controls.
Conclusion
In the context of gestational diabetes, FenoF appears to be a promising therapeutic candidate for improving glucose and lipid homeostasis, protecting hepatic tissue from diabetes-induced damage and inflammation, and enhancing key metabolic pathways in the offspring of GDM rats.
{"title":"Long-term effects of fenofibrate in male offspring of gestational diabetic rats: Evaluation of glycemia, lipid profiles, liver tissue, and metabolic alterations","authors":"Shan Wang , Lin Qin , Xiaoli Song , Hejia Yin , Weihong Yang , Robabe Bazesh","doi":"10.1016/j.prp.2025.156331","DOIUrl":"10.1016/j.prp.2025.156331","url":null,"abstract":"<div><h3>Introduction</h3><div>Fenofibrate (FenoF) has demonstrated potential in regulating glycemia and lipid profiles across various metabolic disorders. However, its effects on the offspring of rats with gestational diabetes mellitus (GDM) have not yet been investigated. This study aims to evaluate the long-term effects of FenoF on glycemic control, lipid metabolism, liver histology, and the expression of key metabolic and inflammatory proteins in the offspring of GDM-exposed rats.</div></div><div><h3>Materials and methods</h3><div>Pregnant Wistar rats were randomly assigned to four groups (n = 4 per group): Control, GDM, FenoF-treated (100 mg/kg/day, orally), and GDM rats treated with FenoF (GDM + FenoF). Diabetes was induced via a single intraperitoneal injection of streptozotocin (50 mg/kg) on gestational day 12. Six male offspring from each group were randomly selected and maintained on a standard chow diet. The offspring were reared until adulthood (12 weeks of age), at which point plasma glucose levels, lipid profiles, and liver tissue alterations were evaluated through histopathological analysis and Western blotting.</div></div><div><h3>Results</h3><div>FenoF treatment significantly reduced triglyceride, low-density lipoprotein cholesterol (LDL-C), and glucose levels (P < 0.05), while significantly increasing high-density lipoprotein cholesterol (HDL-C) levels (P < 0.05) in the offspring of GDM rats. FenoF exerted an ameliorative effect in GDM rat offspring, as evidenced by a significant reduction in hepatic TNF-α expression (P < 0.001) and a marked increase in PPARα levels (P < 0.001) compared to the untreated GDM group. Western blot analysis revealed that FenoF treatment significantly downregulated TLR4 and NF-κB expression, indicating attenuation of inflammatory signaling. Moreover, FenoF treatment significantly upregulated AKT1, IRS1, and CPT1A levels, suggesting enhanced insulin signaling and lipid metabolism. Additionally, Histopathological analysis demonstrated that FenoF preserved liver architecture and significantly reduced inflammation and structural abnormalities relative to GDM controls.</div></div><div><h3>Conclusion</h3><div>In the context of gestational diabetes, FenoF appears to be a promising therapeutic candidate for improving glucose and lipid homeostasis, protecting hepatic tissue from diabetes-induced damage and inflammation, and enhancing key metabolic pathways in the offspring of GDM rats.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156331"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775393","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}
Oncolytic adenoviruses (OADVs) have emerged as promising therapeutics for cancer treatment, offering tumour-selective replication and potent antitumor effects. These genetically engineered viruses infect and lyse cancer cells while simultaneously activating antitumor immunity. OADV can be engineered with therapeutic genes and tumour-specific promoters, further enhancing their specificity and efficacy. Various researchers have explored the use of OADV in cancer treatment, integrating direct oncolysis with immune activation, hence revealing promising therapeutic effects in preclinical studies. This review provides comprehensive insights into the mechanism of OADV engineering with tumor-specific promoters and therapeutic payloads, emphasizing advances in vector design that enhance specificity and efficacy. Key evidence from preclinical and clinical studies across lungs, pancreatic, hepatic, breast, renal, and brain cancers is highlighted, demonstrating the translational impact of OADV therapy. The synergistic potential of OADVs in combination regimens, including chemotherapy, immunotherapy, and gene therapy, is critically appraised. The review further examines central hurdles such as antiviral immunity, tumor microenvironment complexity, and delivery challenges, discussing innovative strategies like genetic modulation and nanoparticle carriers to overcome these barriers. Through integrating direct oncolysis and immune modulation, OADVs offer a multifaceted approach for the treatment of resistant and heterogeneous malignancies. The future of OADV therapy requires continued refinement in vector engineering, personalized delivery systems, and multidisciplinary research, positioning OADVs as pivotal agents for enhancing patient outcomes and quality of life in cancer care.
{"title":"Overcoming barriers in cancer therapy with oncolytic adenoviruses: Engineering strategies and clinical perspectives","authors":"Rohit Sharma , Rahul Sharma , Kamal Dua , Gaurav Gupta , Dinesh Kumar Chellappan , Sachin Kumar Singh , Thakur Gurjeet Singh , Poonam Negi","doi":"10.1016/j.prp.2026.156351","DOIUrl":"10.1016/j.prp.2026.156351","url":null,"abstract":"<div><div>Oncolytic adenoviruses (OADVs) have emerged as promising therapeutics for cancer treatment, offering tumour-selective replication and potent antitumor effects. These genetically engineered viruses infect and lyse cancer cells while simultaneously activating antitumor immunity. OADV can be engineered with therapeutic genes and tumour-specific promoters, further enhancing their specificity and efficacy. Various researchers have explored the use of OADV in cancer treatment, integrating direct oncolysis with immune activation, hence revealing promising therapeutic effects in preclinical studies. This review provides comprehensive insights into the mechanism of OADV engineering with tumor-specific promoters and therapeutic payloads, emphasizing advances in vector design that enhance specificity and efficacy. Key evidence from preclinical and clinical studies across lungs, pancreatic, hepatic, breast, renal, and brain cancers is highlighted, demonstrating the translational impact of OADV therapy. The synergistic potential of OADVs in combination regimens, including chemotherapy, immunotherapy, and gene therapy, is critically appraised. The review further examines central hurdles such as antiviral immunity, tumor microenvironment complexity, and delivery challenges, discussing innovative strategies like genetic modulation and nanoparticle carriers to overcome these barriers. Through integrating direct oncolysis and immune modulation, OADVs offer a multifaceted approach for the treatment of resistant and heterogeneous malignancies. The future of OADV therapy requires continued refinement in vector engineering, personalized delivery systems, and multidisciplinary research, positioning OADVs as pivotal agents for enhancing patient outcomes and quality of life in cancer care.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156351"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912594","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号