American Journal of Pathology最新文献

Insights from the Seminal Findings from Puhr et al on the Mechanisms of Docetaxel Resistance in Prostate Cancer

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-24 DOI: 10.1016/j.ajpath.2024.08.015

Zoran Culig

引用次数: 0

Zinc Finger Protein Znf296 Is a Cardiac-Specific Splicing Regulator Required for Cardiomyocyte Formation. 锌指蛋白 Znf296 是心肌细胞形成所需的心脏特异性剪接调节因子。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-22 DOI: 10.1016/j.ajpath.2025.02.006

Xianpeng Li, Shuaiqi Yang, Lu Wang, Xiangmin Zhang, Ailong Zhang, Yunchao Wang, De-Li Shi, Hongyan Li

{"title":"Zinc Finger Protein Znf296 Is a Cardiac-Specific Splicing Regulator Required for Cardiomyocyte Formation.","authors":"Xianpeng Li, Shuaiqi Yang, Lu Wang, Xiangmin Zhang, Ailong Zhang, Yunchao Wang, De-Li Shi, Hongyan Li","doi":"10.1016/j.ajpath.2025.02.006","DOIUrl":"10.1016/j.ajpath.2025.02.006","url":null,"abstract":"Heart formation and function are tightly regulated at transcriptional and post-transcriptional levels. The dysfunction of cardiac cell-specific regulatory genes leads to various heart diseases. Heart failure is one of the most severe and complex cardiovascular diseases, which could be fatal if not treated promptly. However, the exact causes of heart failure are still unclear, especially at the level of single-gene causation. Here, an essential role is uncovered for the zinc finger protein Znf296 in heart development and cardiac contractile function. Specifically, znf296-deficient zebrafish embryos display heart defects characterized by decreased systolic and diastolic capacities of the ventricle and atrium. This is associated with reduced numbers and disrupted structural integrity of cardiomyocytes, including disorganized cytoskeleton and absence of sarcomeres. Mechanistically, the loss of Znf296 alters the alternative splicing of a subset of genes important for heart development and disease, such as mef2ca, sparc, tpm2, camk2g1, tnnt3b, and pdlim5b. Furthermore, it is demonstrated that Znf296 biochemically and functionally interacts with Myt1la in regulating cardiac-specific splicing and heart development. Importantly, it is shown that ZNF296 also regulates alternative splicing in human cardiomyocytes to maintain structural integrity. These results suggest that Znf296 plays a conserved role for the differentiation of cardiomyocytes and the proper function of the cardiovascular system.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690879","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 Microbial Metabolite δ-Valerobetaine Strengthens the Gut Epithelial Barrier.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-22 DOI: 10.1016/j.ajpath.2025.02.007

Lauren C Askew, C Anthony Gacasan, Maria E Barbian, Jaclyn Weinberg, Liping Luo, Brian S Robinson, Dean P Jones, Christopher D Scharer, Rheinallt M Jones

{"title":"The Microbial Metabolite δ-Valerobetaine Strengthens the Gut Epithelial Barrier.","authors":"Lauren C Askew, C Anthony Gacasan, Maria E Barbian, Jaclyn Weinberg, Liping Luo, Brian S Robinson, Dean P Jones, Christopher D Scharer, Rheinallt M Jones","doi":"10.1016/j.ajpath.2025.02.007","DOIUrl":"10.1016/j.ajpath.2025.02.007","url":null,"abstract":"Metabolic processes within gut microbes generate bioactive metabolites that impact intestinal epithelial barrier function. Using gnotobiotic mice and mass spectrometry-based metabolomics, novel metabolites in host tissues that are of microbial origin were identified. Of those detected, it was shown that the gut microbe-generated metabolite δ-valerobetaine (δ-VB) is a potent inhibitor of l-carnitine biosynthesis and a modulator of fatty acid oxidation by mitochondria in liver cells. In the current study, the bioactivity of δ-VB toward gut epithelial barrier function was assessed. Germ-free mice are devoid of δ-VB, and administration of δ-VB to germ-free mice also induces the enrichment of transcript sets associated with gut mitochondrial respiration and fatty acid oxidation in colonic tissue. Furthermore, δ-VB induces the differential expression of genes that function in barrier function in germ-free and conventionally raised mice. Functionally, δ-VB decreased gut barrier permeability and augmented wound healing in cultured gut epithelial cells and elicited cytoprotective and prorestitutive effects in a mouse model of colonic injury. We conclude that the microbial-derived metabolite δ-VB is a modulator of gut epithelium function, and thus is a molecular target to potentially manage microbiome-host dysbiosis in intestinal health and disease.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690875","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

Machine Learning and Mendelian Randomization Reveal a Tumor Immune Cell Profile for Predicting Bladder Cancer Risk and Immunotherapy Outcomes.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-21 DOI: 10.1016/j.ajpath.2025.01.016

Fei Teng, Renjie Zhang, Yunyi Wang, Qian Li, Bei Wang, Huijing Chen, Tongtong Liu, Zehua Liu, Jia Meng, Shilei Dong, Ce Wang, Yanhong Li

{"title":"Machine Learning and Mendelian Randomization Reveal a Tumor Immune Cell Profile for Predicting Bladder Cancer Risk and Immunotherapy Outcomes.","authors":"Fei Teng, Renjie Zhang, Yunyi Wang, Qian Li, Bei Wang, Huijing Chen, Tongtong Liu, Zehua Liu, Jia Meng, Shilei Dong, Ce Wang, Yanhong Li","doi":"10.1016/j.ajpath.2025.01.016","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.01.016","url":null,"abstract":"The objective of this study is to develop predictive models for bladder cancer (BLCA) using tumor infiltrated immune cell (TIIC)-related genes. Multiple RNA expression data and scRNA-seq were downloaded from TCGA and GEO databases. We calculated tissue specificity index (TSI) and developed a computational framework to identify TIIC signature score based on 3 algorithms. Univariate Cox analysis was performed and TIIC-related model was generated by 20 machine learning algorithms. A significant correlation between TIIC signature score and survival status, tumor stage, and TNM staging system was found. Patients with BLCA in high-score group had more favorable survival outcomes and enhanced response to PD-L1 immunotherapy. Our TIIC model shows better performance in predicting prognosis of BLCA. Diverse frequencies of mutations were observed in human chromosomes across groups categorized by TIIC score. There was no statistically significant correlation observed between non-cancerous bladder conditions and bladder cancer when examining the SNPs associated with the genes in the prognostic model. However, a statistically significant association was found at the SNP sites of rs3763840. There was no significant association between bladder stone and bladder cancer, but there was a significant association on the SNP sites of rs3763840. In conclusion, we constructed a novel TIIC signature score for the prognosis and immunotherapy for BLCA, which offers direction for predicting the OS of patients with BLCA.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690869","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

Glycosylation triggers Cathepsin D maturation and secretion to promote gastric cancer development.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-21 DOI: 10.1016/j.ajpath.2025.02.009

Liling Niu, Xunzhu Zhou, Deman Li, Yongye Zheng, Hui Li

{"title":"Glycosylation triggers Cathepsin D maturation and secretion to promote gastric cancer development.","authors":"Liling Niu, Xunzhu Zhou, Deman Li, Yongye Zheng, Hui Li","doi":"10.1016/j.ajpath.2025.02.009","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.02.009","url":null,"abstract":"Cathepsin D (CTSD) is a lysosomal aspartic protease with high expression in cancers. CTSD localized in different subcellular regions performs distinct roles. However, the precise regulation of its intracellular trafficking and extracellular secretion remains incompletely understood. In this study, it was demonstrated that glycosylation modifications of CTSD determine its maturation and secretion in gastric cancer (GC) cells. Specifically, glycosylation at asparagine 134 (N134) dictated the intracellular trafficking and maturation of CTSD within lysosomes, through facilitating its sorting into COPII vesicles. Glycosylation at asparagine 263 (N263) was essential for the secretion of pro-CTSD, via a novel pathway dependent on the small GTPase Rab3D. Notably, the extracellular release of pro-CTSD occurred more rapidly than its intracellular trafficking from the endoplasmic reticulum (ER) to lysosomes. This enhanced secretion speed may rapidly elevate the levels of pro-CTSD in the tumor microenvironment, in response to extracellular stimuli. Ultimately, glycosylation at N134 and N263 regulated the autophagy and cell proliferation respectively. These findings demonstrate the role of glycosylation in triggering the maturation and secretion of CTSD in GC cells. Through modulating its cellular trafficking, differential glycosylation modifications of CTSD defined the malignant behavior of GC cells.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690858","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

Human MUC2 mucin-producing colonic goblet-like cells secrete the chemokine CXCL8 by activating multiple pro-inflammatory pathways in response to Entamoeba histolytica. 人类 MUC2 粘蛋白产生的结肠鹅膏样细胞通过激活多种促炎途径分泌趋化因子 CXCL8，以应对组织溶解性肠虫。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-21 DOI: 10.1016/j.ajpath.2025.02.008

Ariel Kim, Hayley Gorman, France Moreau, Mackenzie McManus, Antoine Dufour, Kris Chadee

{"title":"Human MUC2 mucin-producing colonic goblet-like cells secrete the chemokine CXCL8 by activating multiple pro-inflammatory pathways in response to Entamoeba histolytica.","authors":"Ariel Kim, Hayley Gorman, France Moreau, Mackenzie McManus, Antoine Dufour, Kris Chadee","doi":"10.1016/j.ajpath.2025.02.008","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.02.008","url":null,"abstract":"The mucus layer produced by highly stressed goblet cells forms a protective shield in the gut to protect the underlying mucosal epithelial cells from external threats. Hypersecretion and depletion of MUC2 mucin from goblet cells is characteristic of symptomatic Entamoeba histolytica (Eh) infections. We hypothesized that MUC2 depleted goblet cells could mount a second line of innate host defence by producing pro-inflammatory cytokines. To investigate this, we determined whether Eh could stimulate pro-inflammatory responses in wild type (WT) high MUC2 mucin-producing goblet-like cells and in CRISPR-Cas9 gene-edited MUC2KO cells. In response to live Eh and soluble Eh proteins, WT and to a lesser extent, MUC2KO cells, produced high levels of CXCL8. Eh temporally induced greater levels of CXCL8 mRNA expression and protein secretion in WT vs MUC2KO cells which was abrogated with alleviation of ER stress with the NADPH-oxidase inhibitor diphenyleneiodonium chloride (DPI). WT cells produced elevated ROS that induced longer half-lives of CXCL8 transcripts which was abrogated with DPI. Western blotting and proteomic analyses revealed that WT, but not MUC2KO cells, were basally primed to respond to external stressors and responded to Eh through rapid activation of the MAPK/ERK, MAPK/p38, and PI3K/Akt pathways, to induce CXCL8. These results suggest that colonic goblet-like cells defend against Eh infections by hypersecreting mucus and to produce the chemokine, CXCL8, to recruit neutrophils.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690862","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 AJP。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-18 DOI: 10.1016/j.ajpath.2025.03.001

引用次数: 0

A Need for Multi-Institutional Collaboration for Deep Learning-Driven Assessment of Osteosarcoma Treatment Response.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-07 DOI: 10.1016/j.ajpath.2025.02.002

David Joon Ho, Narasimhan P Agaram, John H Healey, Meera R Hameed

引用次数: 0

Toll-Interacting Protein Down-Regulation by Cigarette Smoke Exposure Impairs Human Lung Defense against Influenza A Virus Infection.

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":"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. We sought to determine if cigarette smoke (CS) exposure down-regulates 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, 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. Our 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.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"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.

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":"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 in vivo. Staining of metastatic and non-metastatic primary human cSCCs, premalignant and benign epidermal lesions, and normal skin for C5aR1 with multiplex immunofluorescence and chromogenic immunohistochemistry revealed increased expression of C5aR1 on the surface of tumor cells and fibroblasts in invasive cSCCs and recessive dystrophic epidermolysis bullosa-associated cSCCs compared with cSCC in situ, 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.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"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