American Journal of Pathology最新文献_第6页

Poly (ADP-Ribose) Polymerase 1 and 2 in B-Cell Lymphoma PARP-1和PARP-2在b细胞淋巴瘤中的致病作用和治疗意义

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-24 DOI: 10.1016/j.ajpath.2025.07.004

Andrea Molina-Alvarez , Blanca Sanchez-Gonzalez , Luis Colomo , José Yélamos

{"title":"Poly (ADP-Ribose) Polymerase 1 and 2 in B-Cell Lymphoma","authors":"Andrea Molina-Alvarez , Blanca Sanchez-Gonzalez , Luis Colomo , José Yélamos","doi":"10.1016/j.ajpath.2025.07.004","DOIUrl":"10.1016/j.ajpath.2025.07.004","url":null,"abstract":"<div><div>B-cell lymphomas represent a heterogeneous group of malignancies characterized by complex genetic, epigenetic, and microenvironmental alterations. Defects in the DNA damage response (DDR) are critical drivers of lymphomagenesis, generating therapeutic vulnerabilities that can be exploited by targeting key DDR regulators, such as poly (ADP-ribose) polymerase-1 (PARP-1) and PARP-2. Preclinical studies demonstrate that DDR-defective B-cell lymphomas are highly sensitive to PARP-1/PARP-2 inhibition, and early-phase clinical trials using nonselective PARP inhibitors, either as monotherapy or in combination with chemotherapy, immunotherapy, or epigenetic agents, have yielded encouraging results. However, emerging evidence reveals that PARP-1 and PARP-2 play distinct roles in B-cell lymphoma pathogenesis: loss of PARP-1 accelerates lymphomagenesis, whereas loss of PARP-2 delays tumor progression. These findings challenge the current paradigm of pan-PARP inhibition and highlight the need for isoform-selective strategies. Although PARP-1–selective inhibitors have entered clinical trials for homologous recombination–deficient tumors, the development of PARP-2–selective inhibitors remains at an early stage. Future research should prioritize the design of PARP-2–targeted therapies, coupled with biomarker-driven patient selection and rational combination strategies that enhance DNA damage and modulate the tumor immune microenvironment. Selectively targeting PARP-2 offers a promising approach to improving outcomes for patients with aggressive, refractory, or relapsed B-cell lymphomas and represents a critical step forward in advancing precision oncology within hematologic malignancies.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1776-1787"},"PeriodicalIF":3.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Importance of Mentorship in Career Development 导师在职业发展中的重要性。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-23 DOI: 10.1016/j.ajpath.2025.07.002

Fred Sanfilippo

{"title":"The Importance of Mentorship in Career Development","authors":"Fred Sanfilippo","doi":"10.1016/j.ajpath.2025.07.002","DOIUrl":"10.1016/j.ajpath.2025.07.002","url":null,"abstract":"<div><div>Receiving guidance and help from mentors is an essential component of career development and planning, especially in academic medicine and biomedical research, where the availability of resources and job opportunities are becoming more challenging. Mentors share their wisdom, experience, content expertise, and networks with mentees to provide ideas and feedback, identify and open opportunities, deal with problems and avoid mistakes, and especially to assist in evaluating the many personal and professional factors involved in decision making about career paths and job options. Identifying, engaging, and utilizing mentors appropriately is a key part of career development, and effective mentorship can come from several sources, including personal interactions, passive role models, and artificial intelligence. Providing mentorship is an important responsibility that includes various risks and benefits that should be clearly understood before the role of mentor is undertaken. Moreover, mentors should carefully assess whom to accept as a mentee by considering the time, skills, and interest needed to meet their own expectations along with those of their prospective mentees. With increasing awareness of the value of mentorship, more academic health centers, medical schools, and departments provide programs to help their students, trainees, faculty, and staff better access, understand, and take advantage of mentorship opportunities, as well as offer programs to enhance the skills and abilities of those interested in being effective mentors.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1758-1765"},"PeriodicalIF":3.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Peroxisome Proliferator–Activated Receptor Agonist IVA337 Alleviates Inflammation and Fibrosis in MASH by Restoring Lipid Homeostasis 过氧化物酶体增殖物激活受体激动剂IVA337通过恢复脂质稳态减轻MASH的炎症和纤维化。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-23 DOI: 10.1016/j.ajpath.2025.06.012

Na Li , Shuai Wu , Xiaodan Li , Meng Yan , Yifu Ding , Lingjuan Zhang , David A. Brenner , Xiao Liu , Tatiana Kisseleva

{"title":"Peroxisome Proliferator–Activated Receptor Agonist IVA337 Alleviates Inflammation and Fibrosis in MASH by Restoring Lipid Homeostasis","authors":"Na Li , Shuai Wu , Xiaodan Li , Meng Yan , Yifu Ding , Lingjuan Zhang , David A. Brenner , Xiao Liu , Tatiana Kisseleva","doi":"10.1016/j.ajpath.2025.06.012","DOIUrl":"10.1016/j.ajpath.2025.06.012","url":null,"abstract":"<div><div>Metabolic dysfunction–associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction–associated steatotic liver disease, is characterized by significant hepatic fibrosis and inflammation. The pan-peroxisome proliferator–activated receptor (pan-PPAR) agonist IVA337 (lanifibranor) has shown potential as an anti-MASH therapeutic, although its mechanisms of action remain incompletely understood. This study explores the effects and mechanisms of IVA337 using two distinct MASH models: two-dimensional (2D) primary human hepatic stellate cells (HSCs) stimulated with transforming growth factor β1 (TGF-β1), and three-dimensional (3D) liver spheroids comprising primary hepatocytes, HSCs, and non-parenchymal cells. In TGF-β1–stimulated HSCs, IVA337 effectively suppressed the expression of fibrosis-related genes, including <em>PAI1, COL1A1,</em> and <em>ACAT2</em>, as well as the inflammatory gene <em>IL</em><em>6</em>. 3D mouse and human liver spheroid models of MASH, characterized by elevated fibrotic gene expression, were established. IVA337 treatment not only attenuated fibrotic gene expression but also restored lipid content in the MASH spheroids, as evidenced by BODIPY staining. Immunostaining further confirmed a reduction in α-smooth muscle actin and collagen 1 levels after IVA337 treatment. Bulk RNA sequencing and Gene Ontology analysis revealed several lipid metabolism–related genes as key effectors downstream of IVA337. In addition, IVA337 modulated multiple signaling pathways, including IL-17, tumor necrosis factor, NF-κB, phosphatidylinositol 3 kinase/protein kinase B, and mitogen-activated protein kinase. Collectively, these findings show that IVA337 effectively mitigates fibrosis development in both 2D and 3D MASH models by restoring lipid homeostasis and regulating crucial fibrotic and inflammatory pathways.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1822-1838"},"PeriodicalIF":3.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AHSA1/Hsp90α Complex Facilitates Microglial Mitophagy by Targeting TOMM70 in Parkinson Disease AHSA1/Hsp90α复合物通过靶向TOMM70在帕金森病中促进小胶质细胞自噬。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-18 DOI: 10.1016/j.ajpath.2025.06.007

Liang Shao , Ji Zhang , Fan Hu , Wen Chai , Yuxuan Zhou , Pengtao Zou , Ping Zhang

{"title":"AHSA1/Hsp90α Complex Facilitates Microglial Mitophagy by Targeting TOMM70 in Parkinson Disease","authors":"Liang Shao , Ji Zhang , Fan Hu , Wen Chai , Yuxuan Zhou , Pengtao Zou , Ping Zhang","doi":"10.1016/j.ajpath.2025.06.007","DOIUrl":"10.1016/j.ajpath.2025.06.007","url":null,"abstract":"<div><div>Parkinson disease (PD) is a commonly diagnosed neurodegenerative disease with rising prevalence globally. However, the pathology of PD remains largely undefined. The aim of this study was to gain a better understanding of microglial mitophagy in PD. A 1-methyl-1,2,3,6-tetrahydropyidine (MPTP)-induced PD mouse model was established and validated by behavior tests. Western blot and immunofluorescence (IF) analyses showed that autophagy was enhanced in MPTP-induced PD mice. IF, quantitative real-time PCR, Western blot, and co-immunoprecipitation analyses also revealed that silencing of heat shock protein 90α (Hsp90α) protected against mitophagy in PD mice. In the microglia/dopaminergic neuron co-culture system, enzyme-linked immunosorbent assay, transmission electron microscopy, JC-1 staining, measurement of ATP content, Annexin V/propidium iodide and fluorescein isothiocyanate staining showed that lack of Hsp90α in MPTP-treated microglia attenuated dopaminergic neuronal death via suppressing mitophagy. IF staining and co-immunoprecipitation confirmed that Hsp90α formed a complex with activator of Hsp90 ATPase activity 1 (AHSA1), and this complex targeted the mitochondrial molecular switch TOMM70 in microglia. The Hsp90α inhibitor geldanamycin and AHSA1 knockdown further revealed that the AHSA1/Hsp90α complex regulated microglial mitophagy by targeting TOMM70 in MPTP-treated microglia and PD mice. In conclusion, the AHSA1/Hsp90α complex facilitated microglial mitophagy by targeting TOMM70 in PD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 11","pages":"Pages 2197-2212"},"PeriodicalIF":3.6,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Current Therapeutic Targets for Alcohol-Associated Liver Disease. 当前酒精相关性肝病的治疗靶点

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-17 DOI: 10.1016/j.ajpath.2025.06.009

Mengmeng Zhang, Jingjing Ji, Jiayi Song, Chenchen An, Wangxiang Pei, Qianwen Fan, Li Zuo, Hua Wang

{"title":"Current Therapeutic Targets for Alcohol-Associated Liver Disease.","authors":"Mengmeng Zhang, Jingjing Ji, Jiayi Song, Chenchen An, Wangxiang Pei, Qianwen Fan, Li Zuo, Hua Wang","doi":"10.1016/j.ajpath.2025.06.009","DOIUrl":"10.1016/j.ajpath.2025.06.009","url":null,"abstract":"<p><p>Alcohol-associated liver disease (ALD) is a liver disorder induced by chronic excessive alcohol consumption, affecting approximately 3.5% of the global population. The spectrum of ALD encompasses simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and the potential development of hepatocellular carcinoma. The pathogenesis of ALD involves a complex interplay of factors, including direct cell damage caused by alcohol and its metabolites, hepatic inflammation, immune dysregulation, and oxidative stress. Additionally, dysbiosis and the subsequent imbalance of gut homeostasis further exacerbate the progression of ALD. While nutritional support and abstinence from alcohol remain the cornerstones of ALD management, increasing evidence highlights the therapeutic potential of targeting various pathologic processes, in particular, inflammation, cellular oxidative stress, lipid metabolism, and strategies that promote liver regeneration and inhibit fibrosis. Moreover, emerging treatment approaches aimed at modulating the gut-liver-brain axis and targeting innate immune cells offer promising new avenues for ALD therapy. For patients with end-stage ALD, liver transplantation remains the only viable option for improving prognosis. This review summarizes the current epidemiology, pathogenesis, pathophysiology, natural history, and recent advancements in the therapeutic management of ALD, aiming to provide further insight into the treatment of ALD and improve patient outcomes.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alcohol-Mediated Skeletal Muscle Adaptations and Their Impact on Comorbidities. 酒精介导的骨骼肌适应及其对合并症的影响

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-17 DOI: 10.1016/j.ajpath.2025.05.025

Keishla M Rodríguez-Graciani, Paticia E Molina, Liz Simon

{"title":"Alcohol-Mediated Skeletal Muscle Adaptations and Their Impact on Comorbidities.","authors":"Keishla M Rodríguez-Graciani, Paticia E Molina, Liz Simon","doi":"10.1016/j.ajpath.2025.05.025","DOIUrl":"10.1016/j.ajpath.2025.05.025","url":null,"abstract":"<p><p>At-risk alcohol use has significant adverse effects on multiple tissue and organ systems, including the skeletal muscle. The pathophysiological mechanisms underlying alcohol-induced dysfunctional skeletal muscle mass are multifactorial, involving decreased protein synthesis, increased protein degradation, impaired glucose homeostasis, bioenergetic dysregulation, aberrant extracellular matrix remodeling, impaired satellite cell function, circadian rhythm disruption, and epigenomic adaptations. This review provides a brief overview of these major alcohol-induced mechanisms of skeletal muscle dysfunction. Additionally, the review examines the current literature on alcohol-mediated skeletal muscle maladaptations in the context of comorbidities such as aging, alcohol-related liver disease, systemic and diet-induced metabolic dysregulation, cancer cachexia, and musculoskeletal pain. Although alcohol-induced skeletal muscle alterations may function as both the cause and consequence of these comorbid conditions, critical research gaps remain, particularly in the need for systematic clinical studies complemented by preclinical mechanistic research. Notably, 40% to 60% of people with at-risk alcohol use exhibit skeletal muscle maladaptations, yet data on associated healthcare or productivity loss costs are lacking. A comprehensive understanding of alcohol-induced skeletal muscle dysfunction is warranted for developing targeted interventions to reduce healthcare costs and improve quality of life in this population.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Parenchymal and Dyshoric Fibrillar Amyloid Pathology in the rTg-D Rat Model of Cerebral Amyloid Angiopathy Type-2 2型脑淀粉样血管病rTg-D大鼠模型的实质和短纤维淀粉样蛋白病理。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-17 DOI: 10.1016/j.ajpath.2025.06.008

Joseph M. Schrader , Feng Xu , Xiaoyue Zhu , Mark Majchrzak , Judianne Davis , William E. Van Nostrand

{"title":"Parenchymal and Dyshoric Fibrillar Amyloid Pathology in the rTg-D Rat Model of Cerebral Amyloid Angiopathy Type-2","authors":"Joseph M. Schrader , Feng Xu , Xiaoyue Zhu , Mark Majchrzak , Judianne Davis , William E. Van Nostrand","doi":"10.1016/j.ajpath.2025.06.008","DOIUrl":"10.1016/j.ajpath.2025.06.008","url":null,"abstract":"<div><div>Cerebral amyloid angiopathy (CAA) is a common age-related disorder, a prominent comorbidity of Alzheimer disease (AD), and causes vascular cognitive impairment and dementia. A previously developed novel transgenic rat model (rTg-D) expresses the human familial CAA Dutch E22Q mutant amyloid β-protein in brain with hemizygous (HEM) animals developing arteriolar CAA type-2 pathology. In this study, homozygous (HOM) rTg-D rats developed more extensive CAA type-2, characterized by abundant fibrillar amyloid accumulation, including parenchymal congophilic plaques and dyshoric vascular amyloid. Similar to the vascular amyloid, fibrillar amyloid plaques in rTg-D HOM rats were predominantly composed of amyloid β40. The rTg-D HOM rats exhibited pronounced astrocytic and microglial responses as well as phosphorylated tau accumulating in surrounding dystrophic neurites and early tangle-like structures. Cerebral proteomic analyses revealed that while rTg-D HEM rats and rTg-D HOM rats shared some common differentially expressed proteins compared with wild-type rats, rTg-D HOM rats exhibited many more elevated proteins. Because the parenchymal fibrillar plaques of rTg-D HOM rats resemble those seen in AD, the cerebral proteomes were compared between rTg-D HOM rats and a transgenic rat model of AD. This analysis showed that they shared many differentially expressed proteins and activated pathways, including activation of transforming growth factor-β1 signaling and swarming of neutrophils. In conclusion, the present findings show that rTg-D HOM rats develop more severe CAA type-2 pathology than rTg-D HEM rats coupled with AD-like pathologic features, making them a valuable model for studying the intersection of vascular amyloidosis and neurodegeneration.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 11","pages":"Pages 2213-2232"},"PeriodicalIF":3.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chronic Alcohol Consumption Enhances the Differentiation Capacity of Hematopoietic Stem and Progenitor Cells into Osteoclast Precursors. 慢性饮酒增强造血干细胞和祖细胞向破骨细胞前体的分化能力。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-17 DOI: 10.1016/j.ajpath.2025.06.010

Hami Hemati, Madison B Blanton, Jude Koura, Rupak Khadka, Kathleen A Grant, Ilhem Messaoudi

{"title":"Chronic Alcohol Consumption Enhances the Differentiation Capacity of Hematopoietic Stem and Progenitor Cells into Osteoclast Precursors.","authors":"Hami Hemati, Madison B Blanton, Jude Koura, Rupak Khadka, Kathleen A Grant, Ilhem Messaoudi","doi":"10.1016/j.ajpath.2025.06.010","DOIUrl":"10.1016/j.ajpath.2025.06.010","url":null,"abstract":"<p><p>Chronic alcohol consumption (CAC) is associated with an enhanced risk of bone fracture, reduced bone density, and osteoporosis. Previous studies, using a rhesus macaque model of voluntary ethanol consumption, have shown that CAC induces functional, transcriptomic, and epigenomic changes in hematopoietic stem and progenitor cells (HSPCs) and their resultant monocytes/macrophages, skewing them toward a hyper-inflammatory response. Here, those studies were extended to investigate alterations in osteoclast development, which, in postnatal life, differentiate from HSPCs and play a critical role in maintaining bone homeostasis. Analysis using spectral flow cytometry revealed a skewing of HSPCs toward granulocyte-monocyte progenitors within the CAC group, concordant with an increased number of colony-forming unit-granulocyte/macrophage colonies. In addition, HSPCs from animals in the CAC group incubated with macrophage colony-stimulating factor and receptor activator of NF-κB ligand were more likely to differentiate into osteoclasts, as evidenced by increased tartrate-resistant acid phosphatase staining and bone resorption activity. Moreover, single-cell RNA sequencing of differentiated HSPCs identified osteoclast-related clusters in the CAC group with enhanced gene expression in pathways associated with cellular response to stimuli, membrane trafficking, and vesicle-mediated transport. Collectively, these data show that CAC enhances the capacity of HSPCs to differentiate into osteoclast precursors. These findings provide critical insights into the mechanisms by which alcohol consumption contributes to reduced bone density.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

This Month in AJP 本月在AJP。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-12 DOI: 10.1016/j.ajpath.2025.07.001

引用次数: 0

From Single-Cancer to Pan-Cancer Prognosis 从单一癌症到泛癌症预后：具有鲁棒泛化能力的多模态深度学习生存分析框架。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-07-10 DOI: 10.1016/j.ajpath.2025.06.006

Binyu Zhang , Shichao Li , Junpeng Jian , Xiaoyu Ren , Ziqi Zhao , Limei Guo , Fei Su , Zhu Meng , Zhicheng Zhao

{"title":"From Single-Cancer to Pan-Cancer Prognosis","authors":"Binyu Zhang , Shichao Li , Junpeng Jian , Xiaoyu Ren , Ziqi Zhao , Limei Guo , Fei Su , Zhu Meng , Zhicheng Zhao","doi":"10.1016/j.ajpath.2025.06.006","DOIUrl":"10.1016/j.ajpath.2025.06.006","url":null,"abstract":"<div><div>Accurate prognosis represents a critical component in oncology research, enabling personalized treatment planning and optimized health care resource use. Although existing prognostic models demonstrate promising performance on restricted data sets, they remain constrained by two limitations: modality-specific architectural designs and cancer type–specific training paradigms that hinder cross-domain generalization. To address these challenges, the Unified Multimodal Pan-Cancer Survival Network (UMPSNet) was introduced, which integrated histopathology images, genomic expression profiles, and four metadata categories through structured text templates. UMPSNet used the optimal transport–based attention for multimodal feature alignment and a guided mixture of expert mechanisms to address cancer-type distribution shifts. Comprehensive evaluation across 3523 whole slide images (<em>n</em> = 2831) spanning five The Cancer Genome Atlas cohorts demonstrated superior predictive performance (mean concordance index = 0.725), surpassing meticulously designed single-cancer models. Notably, in zero-shot transfer evaluation involving 392 pancreatic adenocarcinoma whole slide images (<em>n</em> = 66) from Peking University Third Hospital, UMPSNet achieved a concordance index of 0.652 without parameter fine-tuning, demonstrating generalization capacity for previously unseen malignancies. Additionally, UMPSNet identified prognostic gene signatures that consistently overlapped with clinically detected mutations (<em>n</em> = 92) while revealing novel gene candidates, validating its clinical relevance and providing complementary insights for precision oncology. Thus, the UMPSNet framework established a new paradigm for multimodal survival analysis by overcoming data heterogeneity and domain shift challenges, thereby providing a clinically adaptable tool for pan-cancer prognostic prediction.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 10","pages":"Pages 1869-1884"},"PeriodicalIF":3.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0