American Journal of Pathology最新文献

Blowing Dust Off the Archives 拂去档案上的灰尘

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-04-23 DOI: 10.1016/j.ajpath.2024.08.016

Richard N. Mitchell

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Title Page 标题页

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-04-01 DOI: 10.1016/S0002-9440(25)00107-5

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Meeting Abstracts 会议摘要

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-04-01 DOI: 10.1016/S0002-9440(25)00109-9

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Insights from the Seminal Findings from Puhr et al on the Mechanisms of Docetaxel Resistance in Prostate Cancer 来自Puhr等人关于前列腺癌多西他赛耐药机制的开创性发现的见解

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

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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. 微生物代谢物三角洲缬罗甜菜碱加强肠道上皮屏障。

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

Glycosylation Triggers Cathepsin D Maturation and Secretion to Promote Gastric Cancer Development. 糖基化触发组织蛋白酶D的成熟和分泌，促进胃癌的发展。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-03-22 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":"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. This study showed 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 secretion of the proenzyme form of CTSD (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 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 show 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":"2025-03-22","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 Mucin-2 Mucin-Producing Colonic Goblet-Like Cells Secrete the Chemokine CXCL8 by Activating Multiple Proinflammatory 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 : 2025-03-22 DOI: 10.1016/j.ajpath.2025.02.008

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

{"title":"Human Mucin-2 Mucin-Producing Colonic Goblet-Like Cells Secrete the Chemokine CXCL8 by Activating Multiple Proinflammatory 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":"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 mucin-2 (MUC2) mucin from goblet cells is characteristic of symptomatic Entamoeba histolytica infections. It was hypothesized that MUC2 depleted goblet cells could mount a second line of innate host defense by producing proinflammatory cytokines. To investigate this, it was determined whether E. histolytica could stimulate proinflammatory responses in wild-type (WT) high MUC2 mucin-producing goblet-like cells and in CRISPR-Cas9 gene-edited MUC2KO cells. In response to live E. histolytica and soluble E. histolytica proteins, WT and, to a lesser extent, MUC2KO cells produced high levels of CXCL8. Entamoeba histolytica temporally induced greater levels of CXCL8 mRNA expression and protein secretion in WT versus MUC2KO cells, which was abrogated with alleviation of endoplasmic reticulum stress with the NADPH-oxidase inhibitor diphenyleneiodonium chloride. WT cells produced elevated reactive oxygen species that induced longer half-lives of CXCL8 transcripts, which was abrogated with diphenyleneiodonium chloride. Western blotting and proteomic analyses revealed that WT cells, but not MUC2KO cells, were basally primed to respond to external stressors and responded to E. histolytica through rapid activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase, mitogen-activated protein kinase/p38, and phosphatidylinositol 3-kinase/Akt pathways, to induce CXCL8. These results suggest that colonic goblet-like cells defend against E. histolytica 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":"2025-03-22","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

Machine Learning and Mendelian Randomization Reveal a Tumor Immune Cell Profile for Predicting Bladder Cancer Risk and Immunotherapy Outcomes. 机器学习和孟德尔随机化揭示了预测膀胱癌风险和免疫治疗结果的肿瘤免疫细胞谱。

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, Ce Wang, Shilei Dong, 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, Ce Wang, Shilei Dong, Yanhong Li","doi":"10.1016/j.ajpath.2025.01.016","DOIUrl":"10.1016/j.ajpath.2025.01.016","url":null,"abstract":"This study's objective was 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 the TCGA and GEO databases. A tissue specificity index was calculated and a computational framework developed to identify TIIC signature scores based on three algorithms. Univariate Cox analysis was performed, and the 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 the high-score group had more favorable survival outcomes and enhanced response to PD-L1 immunotherapy. This TIIC model shows better performance in prognosing BLCA. Diverse frequencies of mutations were observed in human chromosomes across groups categorized by TIIC score. There was no statistically significant correlation observed between noncancerous bladder conditions and BLCA when examining the single nucleotide polymorphisms (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 stones and BLCA, but there was a significant association on the SNP sites of rs3763840. In conclusion, a novel TIIC signature score has been constructed for the prognosis and immunotherapy for BLCA, which offers direction for predicting overall survival 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}

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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

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