American Journal of Pathology最新文献_第8页

Toll-Interacting Protein Down-Regulation by Cigarette Smoke Exposure Impairs Human Lung Defense against Influenza A Virus Infection 暴露于香烟烟雾中的TOLLIP下调会损害人体肺部对甲型流感病毒感染的防御能力。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-06 DOI: 10.1016/j.ajpath.2025.02.005

Hina Agraval , Junfeng Gao , Niccolette Schaunaman , Huang Hua , R. William Vandivier , Mari Numata , Brian J. Day , Hong Wei Chu

{"title":"Toll-Interacting Protein Down-Regulation by Cigarette Smoke Exposure Impairs Human Lung Defense against Influenza A Virus Infection","authors":"Hina Agraval , Junfeng Gao , Niccolette Schaunaman , Huang Hua , R. William Vandivier , Mari Numata , Brian J. Day , Hong Wei Chu","doi":"10.1016/j.ajpath.2025.02.005","DOIUrl":"10.1016/j.ajpath.2025.02.005","url":null,"abstract":"<div><div>Cigarette smoking is a primary cause of chronic obstructive pulmonary disease (COPD). Smokers have a higher risk of influenza-related mortality, but the underlying mechanisms remain unclear. Toll-interacting protein (TOLLIP), an immune regulator, inhibits influenza A virus (IAV) infection, but its regulation in COPD has not been well understood. This study was designed to determine whether cigarette smoke (CS) exposure down-regulated TOLLIP expression via epigenetic mechanisms, including histone methylation. TOLLIP and histone-methylating enzymes enhancer of zeste homolog 1/2 (EZH1/2) were measured in healthy and COPD human lungs, human airway epithelial cells cultured under submerged and air-liquid interface conditions, and precision-cut lung slices (PCLSs) exposed to CS with or without IAV infection. EZH1/2 siRNA and inhibitors were used to investigate their effects on TOLLIP expression. In patients with COPD, TOLLIP levels decreased, whereas EZH1 and EZH2 expression increased. Repeated CS exposure decreased TOLLIP and increased EZH1, EZH2, trimethylation of histone H3 at lysine 27 (H3K27me3), and IAV levels in human airway epithelial cells and PCLSs. EZH1/2 siRNA or their pharmacologic inhibitor valemetostat tosylate, in part, restored TOLLIP and reduced IAV levels in CS-exposed airway epithelial cells and PCLSs. These findings suggest that repeated CS exposure during viral infection reduced TOLLIP levels and increased viral load in part through EZH1/EZH2-H3K27me3–mediated epigenetic mechanisms. Targeting EZH1 and EZH2 may serve as one of the potential therapeutic strategies to restore TOLLIP expression and host defense against viral infections in patients with COPD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 6","pages":"Pages 1124-1140"},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584326","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

C5aR1 Promotes Invasion, Metastasis, and Poor Prognosis in Cutaneous Squamous Cell Carcinoma C5aR1促进皮肤鳞状细胞癌的侵袭、转移和不良预后

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-06 DOI: 10.1016/j.ajpath.2025.02.004

Lauri Heiskanen , Liisa Nissinen , Elina Siljamäki , Jaakko S. Knuutila , Teijo Pellinen , Markku Kallajoki , Jyrki Heino , Pilvi Riihilä , Veli-Matti Kähäri

{"title":"C5aR1 Promotes Invasion, Metastasis, and Poor Prognosis in Cutaneous Squamous Cell Carcinoma","authors":"Lauri Heiskanen , Liisa Nissinen , Elina Siljamäki , Jaakko S. Knuutila , Teijo Pellinen , Markku Kallajoki , Jyrki Heino , Pilvi Riihilä , Veli-Matti Kähäri","doi":"10.1016/j.ajpath.2025.02.004","DOIUrl":"10.1016/j.ajpath.2025.02.004","url":null,"abstract":"<div><div>Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and the metastatic from is associated with a poor prognosis. Here, the role of the complement C5a receptor C5aR1 was examined in the progression and metastasis of cSCC. C5aR1 expression was increased in cSCC cells in a three-dimensional spheroid coculture model in the presence of fibroblasts, and treatment with recombinant C5a enhanced the invasion of cSCC cells. Staining for C5aR1 was detected on the surface of tumor cells at the invasive edge of human cSCC xenografts <em>in vivo</em>. Metastatic and non-metastatic primary human cSCCs, premalignant and benign epidermal lesions, and normal skin for C5aR1 were stained with multiplex immunofluorescence and chromogenic immunohistochemistry. Increased expression of C5aR1 was observed on the surface of tumor cells and fibroblasts in invasive cSCCs and recessive dystrophic epidermolysis bullosa–associated cSCCs compared with cSCC <em>in situ</em>, actinic keratoses, seborrheic keratoses, and normal skin. Increased expression of C5aR1 on the tumor cell surface and in fibroblasts was associated with metastatic risk and poor disease-specific survival of patients with primary cSCC. These findings suggest a role of C5a in cSCC cell invasion, and they identify C5aR1 as a novel biomarker for metastasis risk and poor prognosis in patients with cSCC. The results also suggest that C5aR1 could be a novel therapeutic target for the treatment of locally advanced and metastatic cSCC.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 6","pages":"Pages 1158-1171"},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584324","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

Hypoxia Contributes to the Early-Stage Progression of Necrotizing Sialometaplasia 缺氧有助于坏死性唾液化生的早期进展。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-06 DOI: 10.1016/j.ajpath.2025.01.015

Shohei Yoshimoto , Naomi Yada , Ayataka Ishikawa , Kenji Kawano , Kou Matsuo , Akimitsu Hiraki , Kazuhiko Okamura

{"title":"Hypoxia Contributes to the Early-Stage Progression of Necrotizing Sialometaplasia","authors":"Shohei Yoshimoto , Naomi Yada , Ayataka Ishikawa , Kenji Kawano , Kou Matsuo , Akimitsu Hiraki , Kazuhiko Okamura","doi":"10.1016/j.ajpath.2025.01.015","DOIUrl":"10.1016/j.ajpath.2025.01.015","url":null,"abstract":"<div><div>Necrotizing sialometaplasia (NSM) is a nonneoplastic lesion listed in the World Health Organization Classification of Tumours–Head and Neck Tumours. In early NSM lesion, there is infarction and necrosis of the acinar cells, and squamous metaplasia of the salivary ducts occurs as the lesion matures. Differentiation from squamous cell carcinoma and other malignancies is sometimes required clinically and histopathologically. Local hypoxia caused by trauma and vascular compromise is a proposed etiology of NSM. However, the mechanisms underlying the pathogenesis are unclear. This study focused on the early stages of NSM. Histopathologic observations revealed that the region showing acinar necrosis contained myoepithelial cells with reticular arrangement. Hypoxic <em>in vitro</em> experiments using mouse salivary gland organoids revealed that myoepithelial and basal cells were more tolerant to hypoxia than acinar cells. Moreover, the residual myoepithelial cells in NSM and hypoxia-tolerant cells in organoids expressed transforming growth factor-β3 (<em>TGFB3</em>), which plays a critical role in cell proliferation and squamous metaplasia. Organoid experiments have also replicated the process of squamous metaplasia in NSM during hypoxia and the resolution of hypoxia. Thus, this study demonstrated that hypoxia is a possible etiology of NSM based on the results of histopathologic and <em>in vitro</em> experimental observations.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 6","pages":"Pages 1074-1084"},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584325","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 Involvement of Mitochondrial Dysfunction during the Development of Adenomyosis 线粒体功能障碍在子宫腺肌症发育过程中的参与。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-24 DOI: 10.1016/j.ajpath.2025.01.014

Nari Kay , Chun-Yen Huang , Ya-Chun Yu , Chih-Chen Chen , Chi-Chang Chang , S. Joseph Huang

{"title":"The Involvement of Mitochondrial Dysfunction during the Development of Adenomyosis","authors":"Nari Kay , Chun-Yen Huang , Ya-Chun Yu , Chih-Chen Chen , Chi-Chang Chang , S. Joseph Huang","doi":"10.1016/j.ajpath.2025.01.014","DOIUrl":"10.1016/j.ajpath.2025.01.014","url":null,"abstract":"<div><div>The etiology of adenomyosis remains unclear. The association between epithelial-mesenchymal transition (EMT) and mitochondrial dysfunction is involved in fibrotic diseases. Adenomyosis is defined as the existence of endometrial glands and stroma in the myometrium with EMT and ultimate fibrosis. This study was designed to investigate the involvement of mitochondrial dysfunction in fibrotic adenomyosis. Mitochondrial integrity was examined in mouse and human adenomyotic tissues. Control and tamoxifen-treated mice were treated with 3-nitropropionic acid (a mitochondrial dysfunction inducer) and NG-nitro-L-arginine methyl ester (a mitochondrial dysfunction inhibitor), respectively, at postnatal day 21, followed by an evaluation of adenomyosis, EMT, and fibrosis as well as the expression of mitophagy, oxidative stress, and transforming growth factor-β1 (TGF-β1). The gene profiles of adenomyotic uteri were examined at postnatal day 42. Adenomyotic mice exhibited increased development of EMT and fibrosis. Adenomyotic tissues showed consistent mitochondrial destruction with increased fission, mitophagosomes, and lysosomes. Besides, mitophagy, oxidative stress, and TGF-β1 levels were consistently increased. The mitochondrial dysfunction, the development of mitophagy and fibrosis, and TGF-β1 expression were induced by 3-nitropropionic acid in control uteri. In contrast, NG-nitro-L-arginine methyl ester attenuated mitochondrial dysfunction, mitophagy, fibrosis, and TGF-β1 in adenomyotic uteri. Gene profiling demonstrated increased expression of mitochondrial dysfunction–related genes in adenomyotic uteri. This indicates that mitochondrial dysfunction–induced TGF-β1 dysregulation and fibrosis are associated with the development of adenomyosis.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 5","pages":"Pages 861-874"},"PeriodicalIF":4.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514412","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

Cholangiocarcinoma as a Biologically Complex and Clinically Challenging Orphan Cancer 胆管癌是一种具有生物学复杂性和临床挑战性的孤儿癌

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-21 DOI: 10.1016/j.ajpath.2024.09.007

Alphonse E. Sirica

引用次数: 0

Reinterpreting the True Cause and Nature of Unexpected Liver Lumps 重新解释意外肝肿块的真正原因和性质

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-21 DOI: 10.1016/j.ajpath.2024.09.012

George K. Michalopoulos

引用次数: 0

Reviewer Acknowledgment 评论家承认

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-21 DOI: 10.1016/j.ajpath.2025.01.002

引用次数: 0

Interferon-γ/Janus Kinase 1/STAT1 Signaling Represses Forkhead Box A1 and Drives a Basal Transcriptional State in Muscle-Invasive Bladder Cancer IFNγ/JAK1/STAT1信号抑制FOXA1并驱动肌肉浸润性膀胱癌的基础转录状态。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-20 DOI: 10.1016/j.ajpath.2025.01.013

Shamara S. Lawrence , Hironobu Yamashita , Lauren Shuman , Jay D. Raman , Monika Joshi , Gregory S. Yochum , Xue-Ru Wu , Hikmat A. Al-Ahmadie , Joshua I. Warrick , Vonn Walter , David J. DeGraff

{"title":"Interferon-γ/Janus Kinase 1/STAT1 Signaling Represses Forkhead Box A1 and Drives a Basal Transcriptional State in Muscle-Invasive Bladder Cancer","authors":"Shamara S. Lawrence , Hironobu Yamashita , Lauren Shuman , Jay D. Raman , Monika Joshi , Gregory S. Yochum , Xue-Ru Wu , Hikmat A. Al-Ahmadie , Joshua I. Warrick , Vonn Walter , David J. DeGraff","doi":"10.1016/j.ajpath.2025.01.013","DOIUrl":"10.1016/j.ajpath.2025.01.013","url":null,"abstract":"<div><div>During progression, luminal muscle-invasive bladder cancer (MIBC) can transition to the aggressive basal-squamous (Ba/Sq) subtype. Reduced expression of forkhead box A1 (<em>FOXA1</em>) in the urothelium is a hallmark and driver of the Ba/Sq transcriptional state and squamous differentiation. Ba/Sq tumors are highly inflamed; however, the specific inflammatory pathways contributing to the Ba/Sq state are unknown. In this study, transcriptomic analyses of The Cancer Genome Atlas MIBC cohort were performed to determine whether immune response gene signatures were associated with MIBC molecular states. Results showed that Ba/Sq MIBCs were enriched for the interferon-γ (IFN-γ)–dominant signature. Ba/Sq MIBCs exhibited increased IFN-γ/Janus kinase (JAK)/STAT pathway activity, corresponding to reduced FOXA1 regulon activity. Immunohistochemistry of MIBC specimens demonstrated that JAK1 expression was significantly increased in tumor areas with squamous differentiation. IFN-γ treatment of luminal MIBC cell lines significantly decreased the expression of luminal transcriptional drivers, including <em>FOXA1</em>, and increased the expression of Ba/Sq markers in a STAT1-dependent manner. RNA-sequencing analyses identified IFN-γ as a driver of the Ba/Sq state. The ability of IFN-γ to repress <em>FOXA1</em> in luminal cells was abrogated by ruxolitinib inhibition of JAK1/2 activity. Additionally, pharmacologic inhibition or genetic ablation of JAK1 restored <em>FOXA1</em> expression in Ba/Sq MIBC cells. These findings are the first to identify IFN-γ as an epithelial cell-extrinsic mechanism to repress <em>FOXA1</em> and drive the Ba/Sq state in MIBC.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 5","pages":"Pages 1013-1030"},"PeriodicalIF":4.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476167","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 Advancements in Digital Neuropathology and Machine Learning for the Study of Neurodegenerative Diseases. 数字神经病理学和机器学习在神经退行性疾病研究中的最新进展。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-13 DOI: 10.1016/j.ajpath.2024.12.018

Dana R Julian, Afshin Bahramy, Makayla Neal, Thomas M Pearce, Julia Kofler

{"title":"Current Advancements in Digital Neuropathology and Machine Learning for the Study of Neurodegenerative Diseases.","authors":"Dana R Julian, Afshin Bahramy, Makayla Neal, Thomas M Pearce, Julia Kofler","doi":"10.1016/j.ajpath.2024.12.018","DOIUrl":"10.1016/j.ajpath.2024.12.018","url":null,"abstract":"<p><p>Computational neurodegenerative neuropathology represents a transformative approach in the analysis and understanding of neurodegenerative diseases through utilization of whole slide images (WSIs) and advanced machine learning/artificial intelligence (ML/AI) techniques. This review explores the emerging field of computational neurodegenerative neuropathology, emphasizing its potential to enhance neuropathologic assessment, diagnosis, and research. Recent advancements in ML/AI technologies have significantly affected image-based medical fields, including anatomic pathology, by automating disease staging, identifying novel morphologic biomarkers, and uncovering new clinical insights via multi-modal AI approaches. Despite its promise, the field faces several challenges, including limited expert annotations, slide scanning inaccessibility, inter-institutional variability, and the complexities of sharing large WSI data sets. This review discusses the importance of improving deep learning model accuracy and efficiency for better interpretation of neuropathologic data. It highlights the potential of unsupervised learning to identify patterns in unannotated data. Furthermore, the development of explainable AI models is crucial for experimental neuropathology. By addressing these challenges and leveraging cutting-edge AI techniques, computational neurodegenerative neuropathology has the potential to revolutionize the field and significantly advance our understanding of disease.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424761","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

Injured Proximal Tubular Epithelial Cells Lose Hepatocyte Nuclear Factor 4α Expression Crucial for Brush Border Formation and Transport 受伤的近端小管上皮细胞失去对刷状边界形成和运输至关重要的HNF4A表达。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-02-13 DOI: 10.1016/j.ajpath.2025.01.011

Michelle Kha , Ylva Magnusson , Iva Johansson , Gülay Altiparmak , Jaana Lundgren , Jenny Nyström , Kerstin Ebefors , Karl Swärd , Martin E. Johansson

{"title":"Injured Proximal Tubular Epithelial Cells Lose Hepatocyte Nuclear Factor 4α Expression Crucial for Brush Border Formation and Transport","authors":"Michelle Kha , Ylva Magnusson , Iva Johansson , Gülay Altiparmak , Jaana Lundgren , Jenny Nyström , Kerstin Ebefors , Karl Swärd , Martin E. Johansson","doi":"10.1016/j.ajpath.2025.01.011","DOIUrl":"10.1016/j.ajpath.2025.01.011","url":null,"abstract":"<div><div>Recent studies have demonstrated that the transcription factor hepatocyte nuclear factor 4α (HNF4A) drives epithelial differentiation in the renal proximal tubules (PTs) and is critical for maintaining a mature PT phenotype. Furthermore, HNF4A down-regulation has been observed following kidney injury in mouse models. The aim of the present work was to investigate the role of HNF4A during acute and chronic human kidney disease and the loss of the mature PT phenotype in cultured PT cells. Loss of HNF4A expression and gain of vimentin expression were reciprocal and gradual during both acute and chronic kidney disease, as indicated by immunohistochemistry. Healthy human kidneys demonstrated partial or total loss of HNF4A expression in vimentin-positive scattered tubular cells. Primary cell isolation and subculture of PT cells recapitulated HNF4A-associated loss of the PT phenotype. Re-expression of HNF4A in cultured PT cells by adenoviral transduction increased transcripts related to brush border formation as well as absorptive and transport processes, as shown by RNA sequencing and gene set enrichment analyses. Thus, the reduction of HNF4A and increase of vimentin expression were connected to both acute and chronic kidney disease and represented a stereotypic injury response of the PT, resulting in dedifferentiation. HNF4A re-expression in cultured primary PT cells could provide a more reliable and predictive <em>in vitro</em> model to study PT function and injury.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 5","pages":"Pages 845-860"},"PeriodicalIF":4.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424710","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