Pub Date : 2025-12-22DOI: 10.1016/j.prp.2025.156341
Monica Armanious, Farida K. Gebreel, Reem W. Algendy, Rahma Hefny, Amira M. Ismail, Patrick M. Maximous, Hend M. El Tayebi
Antibody-drug conjugates (ADCs) initiated a pivotal therapeutic strategy in hematologic malignancies, by combining targeted cytotoxicity with high specificity and reduced systemic toxicity. However, despite promising clinical outcomes, resistance to ADCs raises a remarkable challenge, limiting their long-term efficacy. This review explored the multiplex mechanisms underlying ADC resistance emerging in different hematologic cancers, including overexpression of drug efflux pumps, antigen loss or downregulation, impaired intracellular trafficking, and altered apoptotic pathways. The review sheds the light on the role of tumor microenvironment in promoting resistance and hindering the ultimate ADCs efficacy as well as emerging strategies to overcome resistance such as combination therapies, next-generation ADCs, and biomarker-driven patient selection. Understanding the molecular basis of ADC resistance is crucial for optimizing treatment regimens and guiding future therapeutic development in hematologic malignancies.
{"title":"Unraveling ADC resistance in hematologic malignancies: Challenges and new frontiers","authors":"Monica Armanious, Farida K. Gebreel, Reem W. Algendy, Rahma Hefny, Amira M. Ismail, Patrick M. Maximous, Hend M. El Tayebi","doi":"10.1016/j.prp.2025.156341","DOIUrl":"10.1016/j.prp.2025.156341","url":null,"abstract":"<div><div>Antibody-drug conjugates (ADCs) initiated a pivotal therapeutic strategy in hematologic malignancies, by combining targeted cytotoxicity with high specificity and reduced systemic toxicity. However, despite promising clinical outcomes, resistance to ADCs raises a remarkable challenge, limiting their long-term efficacy. This review explored the multiplex mechanisms underlying ADC resistance emerging in different hematologic cancers, including overexpression of drug efflux pumps, antigen loss or downregulation, impaired intracellular trafficking, and altered apoptotic pathways. The review sheds the light on the role of tumor microenvironment in promoting resistance and hindering the ultimate ADCs efficacy as well as emerging strategies to overcome resistance such as combination therapies, next-generation ADCs, and biomarker-driven patient selection. Understanding the molecular basis of ADC resistance is crucial for optimizing treatment regimens and guiding future therapeutic development in hematologic malignancies.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156341"},"PeriodicalIF":3.2,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878788","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 : 2025-12-20DOI: 10.1016/j.prp.2025.156340
Xiongjie He , Tilong Huang , Ai Yang , Yafang Li , Liping Bai , Yanmei Chen , Jie Bai , Xianwen Zhang
Parkinson’s disease (PD) is a neurodegenerative disorder marked by the accumulation of alpha-synuclein protein within dopamine-producing neurons and their consequent death. Although the specific etiology of PD remains unclear, emerging evidences suggest that disrupted neurogenesis plays a crucial role in pathophysiology of PD. Neurogenesis has a regenerative effect and is a promising therapeutic target for PD. Recent studies demonstrated that impaired neurogenesis in the subventricular zone (SVZ), hippocampus (HIP) and substantia nigra (SN) contributed to motor/nonmotor deficits in PD. However, the precise correlation between the pathogenesis of PD and neurogenesis remains to be explored. This study aimed to investigate the role of the dopaminergic signaling pathway, neurotrophic factors, gut microbiota, neuroinflammation, and mutations in PD-related genes in adult neurogenesis in PD. First, a comprehensive review of recent studies was carried out to explore how neurogenesis impacts PD pathophysiology. Then, the challenges and future perspectives associated with promoting endogenous neurogenesis to compensate for the loss of dopaminergic neurons in PD were investigated. The study offers promising therapeutic strategies to activate the endogenous neurogenesis in PD. Furthermore, it offers promising therapeutic strategies to activate the endogenous neurogenesis in PD. This article also emphasizes the importance of the precise manipulation of neurogenesis in PD with the aim of promoting the translation of these findings into clinical treatment.
{"title":"Adult neurogenesis dysfunction in Parkinson’s disease: Molecular pathology and functional implications","authors":"Xiongjie He , Tilong Huang , Ai Yang , Yafang Li , Liping Bai , Yanmei Chen , Jie Bai , Xianwen Zhang","doi":"10.1016/j.prp.2025.156340","DOIUrl":"10.1016/j.prp.2025.156340","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is a neurodegenerative disorder marked by the accumulation of alpha-synuclein protein within dopamine-producing neurons and their consequent death. Although the specific etiology of PD remains unclear, emerging evidences suggest that disrupted neurogenesis plays a crucial role in pathophysiology of PD. Neurogenesis has a regenerative effect and is a promising therapeutic target for PD. Recent studies demonstrated that impaired neurogenesis in the subventricular zone (SVZ), hippocampus (HIP) and substantia nigra (SN) contributed to motor/nonmotor deficits in PD. However, the precise correlation between the pathogenesis of PD and neurogenesis remains to be explored. This study aimed to investigate the role of the dopaminergic signaling pathway, neurotrophic factors, gut microbiota, neuroinflammation, and mutations in PD-related genes in adult neurogenesis in PD. First, a comprehensive review of recent studies was carried out to explore how neurogenesis impacts PD pathophysiology. Then, the challenges and future perspectives associated with promoting endogenous neurogenesis to compensate for the loss of dopaminergic neurons in PD were investigated. The study offers promising therapeutic strategies to activate the endogenous neurogenesis in PD. Furthermore, it offers promising therapeutic strategies to activate the endogenous neurogenesis in PD. This article also emphasizes the importance of the precise manipulation of neurogenesis in PD with the aim of promoting the translation of these findings into clinical treatment.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156340"},"PeriodicalIF":3.2,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820492","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 : 2025-12-17DOI: 10.1016/j.prp.2025.156333
Jinlin Wang , Kai Zhang , Chen Zheng , Xiao Chen
Background
m6A modification is important in cancer progression. In the research, we explored the functions and mechanisms of WTAP (the key component of m6A) in HCC.
Methods
Expression of WTAP and ITGB4 was examined by qRT-PCR, western blot and IHC assays. Tumor cell proliferation, apoptosis, metastasis and stemness were investigated via colony formation, flow cytometry, transwell and sphere formation assays. The interaction between WTAP and ITGB4 was estimated by RIP, meRIP and dual-luciferase reporter experiments.
Results
ITGB4 was upregulated in HCC. Knockdown of ITGB4 repressed HCC cell growth, motility and stemness, accelerated HCC cell apoptosis in vitro, and blocked tumorigenesis in vivo. Through SRAMP website and a series experiments, WTAP catalysed m6A modification on ITGB4 mRNA, recognized by the reader YTHDF1, leading to increased mRNA stability. WTAP overexpression aggravated the malignant behaviors and stemness of HCC cells, with ITGB4 deficiency abrogated the effects. In addition, we demonstrated that WTAP could activate FAK/PI3K/AKT signaling pathway via regulating ITGB4 expression.
Conclusion
WTAP mediated the m6A methylation modification of ITGB4 to promote HCC progression and tumor stemness, providing a new idea for HCC therapy.
{"title":"WTAP contributes to the malignancy and stemness of hepatocellular carcinoma through upregulating N6-methyladenosine modification of ITGB4","authors":"Jinlin Wang , Kai Zhang , Chen Zheng , Xiao Chen","doi":"10.1016/j.prp.2025.156333","DOIUrl":"10.1016/j.prp.2025.156333","url":null,"abstract":"<div><h3>Background</h3><div>m6A modification is important in cancer progression. In the research, we explored the functions and mechanisms of WTAP (the key component of m6A) in HCC.</div></div><div><h3>Methods</h3><div>Expression of WTAP and ITGB4 was examined by qRT-PCR, western blot and IHC assays. Tumor cell proliferation, apoptosis, metastasis and stemness were investigated via colony formation, flow cytometry, transwell and sphere formation assays. The interaction between WTAP and ITGB4 was estimated by RIP, meRIP and dual-luciferase reporter experiments.</div></div><div><h3>Results</h3><div>ITGB4 was upregulated in HCC. Knockdown of ITGB4 repressed HCC cell growth, motility and stemness, accelerated HCC cell apoptosis <em>in vitro</em>, and blocked tumorigenesis <em>in vivo</em>. Through SRAMP website and a series experiments, WTAP catalysed m6A modification on ITGB4 mRNA, recognized by the reader YTHDF1, leading to increased mRNA stability. WTAP overexpression aggravated the malignant behaviors and stemness of HCC cells, with ITGB4 deficiency abrogated the effects. In addition, we demonstrated that WTAP could activate FAK/PI3K/AKT signaling pathway via regulating ITGB4 expression.</div></div><div><h3>Conclusion</h3><div>WTAP mediated the m6A methylation modification of ITGB4 to promote HCC progression and tumor stemness, providing a new idea for HCC therapy.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156333"},"PeriodicalIF":3.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840857","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}
Lysine demethylase 2A (KDM2A), a crucial member of the histone demethylase family, plays a vital role in epigenetic regulation by modifying histone methylation and the chromatin structure. It regulates key cellular activities, including development, differentiation, and metabolism, by controlling gene expression and transcriptional silencing, and maintaining genomic stability through the demethylation of histone H3 at lysine 36 (H3K36). In addition to its canonical enzymatic role, KDM2A is involved in diverse biological processes, together with embryonic development, stem cell maintenance, DNA damage response, and metabolic homeostasis. Throughout development, it facilitates gene silencing and activation by engaging DNA regions rich in cytosine-guanine (CpG) dinucleotides and attracting polycomb repressive complexes (PRC), which affect lineage specification and organogenesis. Here, we outline the disease-related effects of KDM2A dysregulation related to developmental disorders, cancers, and metastasis. KDM2A aids in tumor development by influencing cell cycle regulators, oncogenes, and chromatin accessibility while also being involved in preserving cancer stem cell characteristics and facilitating epithelial-mesenchymal transition (EMT), metabolic reprogramming, and interactions with cancer-associated fibroblasts (CAFs). Its dual function as an oncogene and tumor suppressor, which varies with the cellular context, highlights its drug complexity and resistance. This review discusses the multifaceted epigenetic functions of KDM2A under both normal and diseased conditions, emphasizing its increasing importance as a potential epigenetic target. It also summarizes the progress in KDM2A-targeted therapies, including inhibitors, RNA interference, CRISPR-Cas9, and immunoepigenetic strategies, with a focus on future applications of KDM2A modulation in clinical treatments for cancer and other epigenetic-associated diseases.
{"title":"KDM2A demethylase: A versatile epigenetic regulator in development, cancer, and therapeutic horizons","authors":"Tajrin Sultana , Md Sadikul Islam , S.M. Abdus Salam , Eshrat Jahan , Md Khalesur Rahman , Md Shiblee Sadik Sabuj , Byung-Yong Park , Tanvir Ahmed , Md Jamilur Rahman , Md Rashedunnabi Akanda","doi":"10.1016/j.prp.2025.156336","DOIUrl":"10.1016/j.prp.2025.156336","url":null,"abstract":"<div><div>Lysine demethylase 2A (KDM2A), a crucial member of the histone demethylase family, plays a vital role in epigenetic regulation by modifying histone methylation and the chromatin structure. It regulates key cellular activities, including development, differentiation, and metabolism, by controlling gene expression and transcriptional silencing, and maintaining genomic stability through the demethylation of histone H3 at lysine 36 (H3K36). In addition to its canonical enzymatic role, KDM2A is involved in diverse biological processes, together with embryonic development, stem cell maintenance, DNA damage response, and metabolic homeostasis. Throughout development, it facilitates gene silencing and activation by engaging DNA regions rich in cytosine-guanine (CpG) dinucleotides and attracting polycomb repressive complexes (PRC), which affect lineage specification and organogenesis. Here, we outline the disease-related effects of KDM2A dysregulation related to developmental disorders, cancers, and metastasis. KDM2A aids in tumor development by influencing cell cycle regulators, oncogenes, and chromatin accessibility while also being involved in preserving cancer stem cell characteristics and facilitating epithelial-mesenchymal transition (EMT), metabolic reprogramming, and interactions with cancer-associated fibroblasts (CAFs). Its dual function as an oncogene and tumor suppressor, which varies with the cellular context, highlights its drug complexity and resistance. This review discusses the multifaceted epigenetic functions of KDM2A under both normal and diseased conditions, emphasizing its increasing importance as a potential epigenetic target. It also summarizes the progress in KDM2A-targeted therapies, including inhibitors, RNA interference, CRISPR-Cas9, and immunoepigenetic strategies, with a focus on future applications of KDM2A modulation in clinical treatments for cancer and other epigenetic-associated diseases.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156336"},"PeriodicalIF":3.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782388","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 : 2025-12-17DOI: 10.1016/j.prp.2025.156337
Xiaoxi Wang , Xiaochen Shen , Moxuan Yang , Ling Yang , Ying He , Yanni Ren , Shuhao Wang , Dayi Wu , Yuanyuan Guo , Yiru Niu , Kaiyue Peng , Zhihui Wang , Jingpeng Wu , Jiacheng Li , Wei Wang , Feng Wang , Lijuan Cui , Wei Wang , Congrong Liu , Dingrong Zhong
Uterine smooth muscle tumors (USMTs) are the most common tumors of the female reproductive system, but remain diagnostically challenging due to morphological overlap among leiomyosarcoma (LMS), various leiomyoma (LM) subtypes, and smooth muscle tumors of uncertain malignant potential (STUMP). This study aimed to develop a weakly supervised artificial intelligence (AI) model for classifying USMTs as benign or malignant using only slide-level labels. A multi-center dataset comprising 94 LMS cases (408 whole-slide images, WSIs) and 634 benign cases (1389 WSIs) was used for model training and internal testing, with an independent external test set including 27 LMS cases (54 WSIs) and 90 benign cases (248 WSIs). The CAMEL2-based model achieved excellent diagnostic performance, with AUCs of 0.9976 and 0.9889 on the internal and external test sets, respectively, and accuracies exceeding 0.97. Heatmaps frequently highlighted regions enriched for key pathological features of LMS, while benign tissues were consistently assigned low-suspicion regions. In STUMP cases, heatmaps emphasized morphologically suspicious regions that often overlapped with areas identified by pathologists, supporting their potential as decision-support visualizations. In the AI–human collaboration study, model assistance was associated with improved diagnostic accuracy and reduced diagnostic time. This represents the first weakly supervised learning model for USMT diagnosis, achieving high accuracy and interpretability with minimal annotation requirements.
{"title":"An interpretable model based on weakly supervised learning for uterine smooth muscle tumor diagnosis: A multi-center study","authors":"Xiaoxi Wang , Xiaochen Shen , Moxuan Yang , Ling Yang , Ying He , Yanni Ren , Shuhao Wang , Dayi Wu , Yuanyuan Guo , Yiru Niu , Kaiyue Peng , Zhihui Wang , Jingpeng Wu , Jiacheng Li , Wei Wang , Feng Wang , Lijuan Cui , Wei Wang , Congrong Liu , Dingrong Zhong","doi":"10.1016/j.prp.2025.156337","DOIUrl":"10.1016/j.prp.2025.156337","url":null,"abstract":"<div><div>Uterine smooth muscle tumors (USMTs) are the most common tumors of the female reproductive system, but remain diagnostically challenging due to morphological overlap among leiomyosarcoma (LMS), various leiomyoma (LM) subtypes, and smooth muscle tumors of uncertain malignant potential (STUMP). This study aimed to develop a weakly supervised artificial intelligence (AI) model for classifying USMTs as benign or malignant using only slide-level labels. A multi-center dataset comprising 94 LMS cases (408 whole-slide images, WSIs) and 634 benign cases (1389 WSIs) was used for model training and internal testing, with an independent external test set including 27 LMS cases (54 WSIs) and 90 benign cases (248 WSIs). The CAMEL2-based model achieved excellent diagnostic performance, with AUCs of 0.9976 and 0.9889 on the internal and external test sets, respectively, and accuracies exceeding 0.97. Heatmaps frequently highlighted regions enriched for key pathological features of LMS, while benign tissues were consistently assigned low-suspicion regions. In STUMP cases, heatmaps emphasized morphologically suspicious regions that often overlapped with areas identified by pathologists, supporting their potential as decision-support visualizations. In the AI–human collaboration study, model assistance was associated with improved diagnostic accuracy and reduced diagnostic time. This represents the first weakly supervised learning model for USMT diagnosis, achieving high accuracy and interpretability with minimal annotation requirements.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156337"},"PeriodicalIF":3.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145798004","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 : 2025-12-16DOI: 10.1016/j.prp.2025.156335
Han Wang , You-Wen Qian , Xia Sheng , Chun-Yan Xia , Hong-Zhen Chen , Zhen-Yu Cao , Hua Yu , Ying-Ying Zhou , Wen-Ming Cong , Miao-Xia He , Hui Dong
Background
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) lacks standardized pathological diagnostic paradigm. The significance of tumor necrosis in cHCC-CCA remains undefined. This study aimed to decipher its role and develop a practical grading system.
Methods
A multicenter analysis was conducted on 307 cHCC-CCA patients. Tumor necrosis was pathologically graded as: TN1 (no necrosis, N = 35), TN2 (focal necrosis; maximum diameter of a single focus ≤0.55 cm/one low-power field, N = 129), and TN3 (extensive necrosis; >0.55 cm, N = 143). Associations between tumor necrosis and clinicopathological features, recurrence-free survival (RFS), overall survival (OS), early RFS (≤2 years), and late RFS (>2 years) were assessed. The impact of postoperative adjuvant transarterial chemoembolization (PA-TACE) was also evaluated.
Results
Higher necrosis grades (TN2/TN3) were significantly associated with aggressive tumor characteristics, including larger tumor size, vascular invasion, and lymph node metastasis. TN3 patients had the worst median RFS (0.28 years) and OS (1.36 years), compared to TN2 (RFS: 0.68 years; OS: 2.64 years) and TN1 (RFS: 1.46 years; OS: not reached). The grading system was an independent prognostic factor for RFS, OS, and early RFS in multivariate analysis. PA-TACE significantly improved early RFS in the TN2/TN3 groups and RFS in the TN3 group specifically, but not in the TN1 group.
Conclusions
Tumor necrosis in cHCC-CCA indicates aggressive tumor biology and poorer outcomes. The proposed three-tier grading system provides robust prognostic stratification. PA-TACE benefits patients with significant necrosis (TN2/TN3), particularly in preventing early recurrence. Standardized assessment of tumor necrosis is recommended to optimize risk stratification and guide adjuvant therapy decisions for cHCC-CCA patients.
背景：肝细胞-胆管合并癌（cHCC-CCA）缺乏标准化的病理诊断模式。肿瘤坏死在cHCC-CCA中的意义尚不明确。本研究旨在解读其作用，并建立一套实用的分级体系。方法：对307例cHCC-CCA患者进行多中心分析。肿瘤坏死病理分级为：TN1（无坏死，N = 35）、TN2（局灶性坏死，单灶最大直径≤0.55 cm/一个低倍视场，N = 129）、TN3（广泛坏死，>0.55 cm, N = 143）。评估肿瘤坏死与临床病理特征、无复发生存期（RFS）、总生存期（OS）、早期RFS（≤2年）和晚期RFS （bb0 ~ 2年）之间的关系。术后辅助经动脉化疗栓塞（PA-TACE）的影响也进行了评估。结果：较高的坏死分级（TN2/TN3）与肿瘤的侵袭性特征显著相关，包括肿瘤大小较大、血管侵犯和淋巴结转移。与TN2 （RFS: 0.68年；OS: 2.64年）和TN1 （RFS: 1.46年；OS：未达到）相比，TN3患者的中位RFS（0.28年）和OS（1.36年）最差。在多变量分析中，分级系统是RFS、OS和早期RFS的独立预后因素。PA-TACE显著改善TN2/TN3组的早期RFS，特别是TN3组的RFS，但TN1组没有。结论：cHCC-CCA肿瘤坏死提示肿瘤生物学侵袭性，预后较差。建议的三层分级系统提供了可靠的预后分层。PA-TACE对显著坏死（TN2/TN3）患者有益，特别是在预防早期复发方面。建议对肿瘤坏死进行标准化评估，以优化风险分层，指导cHCC-CCA患者的辅助治疗决策。
{"title":"Deciphering the significance of tumor necrosis and developing a grading system in combined hepatocellular-cholangiocarcinoma: A multicenter pathological study","authors":"Han Wang , You-Wen Qian , Xia Sheng , Chun-Yan Xia , Hong-Zhen Chen , Zhen-Yu Cao , Hua Yu , Ying-Ying Zhou , Wen-Ming Cong , Miao-Xia He , Hui Dong","doi":"10.1016/j.prp.2025.156335","DOIUrl":"10.1016/j.prp.2025.156335","url":null,"abstract":"<div><h3>Background</h3><div>Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) lacks standardized pathological diagnostic paradigm. The significance of tumor necrosis in cHCC-CCA remains undefined. This study aimed to decipher its role and develop a practical grading system.</div></div><div><h3>Methods</h3><div>A multicenter analysis was conducted on 307 cHCC-CCA patients. Tumor necrosis was pathologically graded as: TN1 (no necrosis, N = 35), TN2 (focal necrosis; maximum diameter of a single focus ≤0.55 cm/one low-power field, N = 129), and TN3 (extensive necrosis; >0.55 cm, N = 143). Associations between tumor necrosis and clinicopathological features, recurrence-free survival (RFS), overall survival (OS), early RFS (≤2 years), and late RFS (>2 years) were assessed. The impact of postoperative adjuvant transarterial chemoembolization (PA-TACE) was also evaluated.</div></div><div><h3>Results</h3><div>Higher necrosis grades (TN2/TN3) were significantly associated with aggressive tumor characteristics, including larger tumor size, vascular invasion, and lymph node metastasis. TN3 patients had the worst median RFS (0.28 years) and OS (1.36 years), compared to TN2 (RFS: 0.68 years; OS: 2.64 years) and TN1 (RFS: 1.46 years; OS: not reached). The grading system was an independent prognostic factor for RFS, OS, and early RFS in multivariate analysis. PA-TACE significantly improved early RFS in the TN2/TN3 groups and RFS in the TN3 group specifically, but not in the TN1 group.</div></div><div><h3>Conclusions</h3><div>Tumor necrosis in cHCC-CCA indicates aggressive tumor biology and poorer outcomes. The proposed three-tier grading system provides robust prognostic stratification. PA-TACE benefits patients with significant necrosis (TN2/TN3), particularly in preventing early recurrence. Standardized assessment of tumor necrosis is recommended to optimize risk stratification and guide adjuvant therapy decisions for cHCC-CCA patients.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156335"},"PeriodicalIF":3.2,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794214","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 : 2025-12-16DOI: 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":"2025-12-16","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 : 2025-12-11DOI: 10.1016/j.prp.2025.156330
Peng Yu , Chen‑xi Li , Zhi‑qiang Song , Zhong‑cheng Gong
Synovitis of the temporomandibular joint (TMJ), a prevalent degenerative joint disease, plays an important role in the pathogenesis of TMJ osteoarthritis. This pathological condition arises from abnormal mechanical loading that induces a chronic low-grade inflammation within the synovial microenvironment through ferroptotic processes. Our research explores the impact of flow fluid-induced shear stress (FFSS) on ferroptosis in fibroblast-like synoviocytes (FLSs) and elucidates the relationship between mechanical overload and the development of TMJ synovitis. Experimental findings revealed progressive alterations in cellular morphology accompanied by significant elevations in intracellular ferrous ion (Fe2 +) concentrations and reactive oxygen species (ROS) levels with increasing FFSS intensity (all p < 0.05). Quantitative analysis showed upregulated expression of pro-inflammatory cytokines (IL-1β, IL-18), matrix-degrading enzymes (MMP-3, MMP-13), and ferroptosis-related markers (ACSL4, Nrf2), while antioxidant defense components (GPX4, system Xc-) were downregulated (all p < 0.05). Pharmacological inhibition using Ferrostatin-1 (Fer-1) significantly attenuated intracellular Fe2+ and ROS accumulation. The treatment group demonstrated reduced expression of IL-1β (p < 0.05) and ACSL4 (p < 0.001), with concomitant upregulation of GPX4 (p < 0.05) and Nrf2 (p < 0.001), though IL-18 modulation did not reach statistical significance (p > 0.05). These results establish that mechanical overload initiates ferroptosis in FLSs, driving inflammatory responses and extracellular matrix degradation through elevated Fe2+ and ROS production, ultimately contributing to TMJ synovitis pathogenesis. Our investigation provides novel mechanistic insights into FFSS-mediated ferroptosis in synovial cells, presenting foundational evidence for developing targeted therapeutic strategies that modulate this cell death pathway to enhance clinical management of TMJ synovitis.
{"title":"Effect of Ferrostatin-1 on temporomandibular joint synovitis induced by abnormal flow fluid shear stress: An in vitro study","authors":"Peng Yu , Chen‑xi Li , Zhi‑qiang Song , Zhong‑cheng Gong","doi":"10.1016/j.prp.2025.156330","DOIUrl":"10.1016/j.prp.2025.156330","url":null,"abstract":"<div><div>Synovitis of the temporomandibular joint (TMJ), a prevalent degenerative joint disease, plays an important role in the pathogenesis of TMJ osteoarthritis. This pathological condition arises from abnormal mechanical loading that induces a chronic low-grade inflammation within the synovial microenvironment through ferroptotic processes. Our research explores the impact of flow fluid-induced shear stress (FFSS) on ferroptosis in fibroblast-like synoviocytes (FLSs) and elucidates the relationship between mechanical overload and the development of TMJ synovitis. Experimental findings revealed progressive alterations in cellular morphology accompanied by significant elevations in intracellular ferrous ion (Fe<sup>2 +</sup>) concentrations and reactive oxygen species (ROS) levels with increasing FFSS intensity (all <em>p</em> < 0.05). Quantitative analysis showed upregulated expression of pro-inflammatory cytokines (IL-1β, IL-18), matrix-degrading enzymes (MMP-3, MMP-13), and ferroptosis-related markers (ACSL4, Nrf2), while antioxidant defense components (GPX4, system Xc-) were downregulated (all <em>p</em> < 0.05). Pharmacological inhibition using Ferrostatin-1 (Fer-1) significantly attenuated intracellular Fe<sup>2+</sup> and ROS accumulation. The treatment group demonstrated reduced expression of IL-1β (<em>p</em> < 0.05) and ACSL4 (<em>p</em> < 0.001), with concomitant upregulation of GPX4 (<em>p</em> < 0.05) and Nrf2 (<em>p</em> < 0.001), though IL-18 modulation did not reach statistical significance (<em>p</em> > 0.05). These results establish that mechanical overload initiates ferroptosis in FLSs, driving inflammatory responses and extracellular matrix degradation through elevated Fe<sup>2+</sup> and ROS production, ultimately contributing to TMJ synovitis pathogenesis. Our investigation provides novel mechanistic insights into FFSS-mediated ferroptosis in synovial cells, presenting foundational evidence for developing targeted therapeutic strategies that modulate this cell death pathway to enhance clinical management of TMJ synovitis.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156330"},"PeriodicalIF":3.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145749026","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 : 2025-12-11DOI: 10.1016/j.prp.2025.156329
Jilong Qin , Longguang Li , Chi Sing Ng , Xiaodong Lin , Xina Lin , Peng Hou , Ping He
Objective
To explore the clinicopathological and immunohistochemical features of primary Rosai-Dorfman disease (RDD) in the lung and mediastinum.
Methods
Histological observation and immunohistochemical staining of 5 cases of pulmonary and mediastinal RDD, with a review of the related literature.
Results
Two cases were located in the trachea with involvement of the lung. One case was located in the left lower lung. Two cases were located in the mediastinum. Macroscopically, 1 case had clear boundaries, while 4 cases had unclear boundaries, and grayish-white on cut surfaces. Microscopically, low power view showing alternating light and dark areas. The dark areas comprise an admixture of lymphocytes and plasma cells. The light areas comprise the characteristic pale pink histiocytic cells. Histiocytes are large with round-to-oval nuclei, dispersed chromatin, prominent nucleoli, and abundant clear-to-foamy or vacuolated cytoplasm. Emperipolesis was observed in all five cases. All five cases showed interstitial fibrosis or sclerosis and Russell bodies. Four cases (4/5, 80 %) showed lymphoid follicles with germinal centers in the interstitium. Four cases showed (4/5, 80 %) interstitial neutrophil infiltration, with three cases accompanied by microabscess formation. Immunophenotypically, the histiocytes expressed Cyclin D1(5/5, 100 %), OCT2 (5/5, 100 %), S100 protein (5/5, 100 %), CD68 (5/5, 100 %), CD163 (5/5, 100 %), BCL2 (5/5, 100 %) and CD30 (3/5, 60 %), but did not express CD1a, Langerin, IgG4 and ALK.
Conclusion
RDD of the lung and mediastinum is rare, with a wide range of ages. Histologically, there are often lymphoid follicles with germinal centers and interstitial fibrosis or sclerosis. This together with the expression of BCL2 and CD30 in the histiocytes can lead to misdiagnosis of lymphomas or other lymphoproliferative diseases or missed diagnosis, particularly in the mediastinum. Careful histological examination for the diagnostic feature of emperipolesis together with characteristic Cyclin D1, OCT2, S100 protein, and CD68 positivity are important clues for accurate diagnosis.
{"title":"Primary Rosai-Dorfman disease of lung and mediastinum: A clinicopathological and immunohistochemical study of five cases","authors":"Jilong Qin , Longguang Li , Chi Sing Ng , Xiaodong Lin , Xina Lin , Peng Hou , Ping He","doi":"10.1016/j.prp.2025.156329","DOIUrl":"10.1016/j.prp.2025.156329","url":null,"abstract":"<div><h3>Objective</h3><div>To explore the clinicopathological and immunohistochemical features of primary Rosai-Dorfman disease (RDD) in the lung and mediastinum.</div></div><div><h3>Methods</h3><div>Histological observation and immunohistochemical staining of 5 cases of pulmonary and mediastinal RDD, with a review of the related literature.</div></div><div><h3>Results</h3><div>Two cases were located in the trachea with involvement of the lung. One case was located in the left lower lung. Two cases were located in the mediastinum. Macroscopically, 1 case had clear boundaries, while 4 cases had unclear boundaries, and grayish-white on cut surfaces. Microscopically, low power view showing alternating light and dark areas. The dark areas comprise an admixture of lymphocytes and plasma cells. The light areas comprise the characteristic pale pink histiocytic cells. Histiocytes are large with round-to-oval nuclei, dispersed chromatin, prominent nucleoli, and abundant clear-to-foamy or vacuolated cytoplasm. Emperipolesis was observed in all five cases. All five cases showed interstitial fibrosis or sclerosis and Russell bodies. Four cases (4/5, 80 %) showed lymphoid follicles with germinal centers in the interstitium. Four cases showed (4/5, 80 %) interstitial neutrophil infiltration, with three cases accompanied by microabscess formation. Immunophenotypically, the histiocytes expressed Cyclin D1(5/5, 100 %), OCT2 (5/5, 100 %), S100 protein (5/5, 100 %), CD68 (5/5, 100 %), CD163 (5/5, 100 %), BCL2 (5/5, 100 %) and CD30 (3/5, 60 %), but did not express CD1a, Langerin, IgG4 and ALK.</div></div><div><h3>Conclusion</h3><div>RDD of the lung and mediastinum is rare, with a wide range of ages. Histologically, there are often lymphoid follicles with germinal centers and interstitial fibrosis or sclerosis. This together with the expression of BCL2 and CD30 in the histiocytes can lead to misdiagnosis of lymphomas or other lymphoproliferative diseases or missed diagnosis, particularly in the mediastinum. Careful histological examination for the diagnostic feature of emperipolesis together with characteristic Cyclin D1, OCT2, S100 protein, and CD68 positivity are important clues for accurate diagnosis.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156329"},"PeriodicalIF":3.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145749025","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}
Precision medicine has transformed healthcare by tailoring treatment plans to an individual’s genetic profile, in contrast to standardized therapies. Patient-derived tumoroids facilitate cancer research, while extracellular vesicles (EVs) provide insights into disease states. EVs from tumoroids serve as diagnostic tools for cancer, reflecting gene mutations and enabling minimally invasive tracking of disease progression. Artificial Intelligence (AI) enhances precision medicine by analyzing extensive datasets derived from tumors and EVs, thereby advancing cancer detection and therapy. The tumor microenvironment (TME) plays a pivotal role in tumor development and is studied using patient-derived organoids (PDOs), which accurately recapitulate tissue function and support drug screening and personalized treatment strategies. Integrating precision medicine with AI-driven analysis of tumoroids and EVs holds the potential to improve patient outcomes and quality of life through personalized treatment approaches.
{"title":"Tumoroid-derived extracellular vesicles for prognosis and therapeutics: A valuable tool in precision medicine","authors":"Vijay Murali Ravi Mythili , ArulJothi Kandasamy Nagarajan , Vasanth Kanth Loganathbabu Thasma , Shriya Pattabiram , Kumaran Kasinathan , Ramya Lakshmi Rajendran , Anand Krishnan , Prakash Gangadaran , Byeong-Cheol Ahn","doi":"10.1016/j.prp.2025.156332","DOIUrl":"10.1016/j.prp.2025.156332","url":null,"abstract":"<div><div>Precision medicine has transformed healthcare by tailoring treatment plans to an individual’s genetic profile, in contrast to standardized therapies. Patient-derived tumoroids facilitate cancer research, while extracellular vesicles (EVs) provide insights into disease states. EVs from tumoroids serve as diagnostic tools for cancer, reflecting gene mutations and enabling minimally invasive tracking of disease progression. Artificial Intelligence (AI) enhances precision medicine by analyzing extensive datasets derived from tumors and EVs, thereby advancing cancer detection and therapy. The tumor microenvironment (TME) plays a pivotal role in tumor development and is studied using patient-derived organoids (PDOs), which accurately recapitulate tissue function and support drug screening and personalized treatment strategies. Integrating precision medicine with AI-driven analysis of tumoroids and EVs holds the potential to improve patient outcomes and quality of life through personalized treatment approaches.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156332"},"PeriodicalIF":3.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145749027","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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