American Journal of Pathology最新文献

A Century of Progress Toward Gut Barrier Targeting Therapies in Inflammatory Diseases 炎症性疾病肠道屏障靶向治疗的一个世纪进展

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-10-24 DOI: 10.1016/j.ajpath.2025.04.021

Manuel B. Braga-Neto , Andrei I. Ivanov

引用次数: 0

Advancing Breast Cancer Management Through an Enhanced Understanding of Disease Heterogeneity from Initiation to Metastasis 通过加深对从发病到转移的疾病异质性的了解来推进乳腺癌的管理

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-10-24 DOI: 10.1016/j.ajpath.2025.08.003

Dennis Jones

引用次数: 0

Novel Insights into Neurodegenerative Diseases 神经退行性疾病的新见解

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-10-24 DOI: 10.1016/j.ajpath.2025.09.002

Steven L. Carroll, Jody Fromm Longo

引用次数: 0

PGE₂ signaling triggers CD31-independent transendothelial migration in vitro and in vivo. PGE2信号在体外和体内触发cd31不依赖的跨内皮迁移。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-10-17 DOI: 10.1016/j.ajpath.2025.09.012

Vanessa Hayashi, Michael A Seidman, William A Muller

{"title":"PGE2 signaling triggers CD31-independent transendothelial migration in vitro and in vivo.","authors":"Vanessa Hayashi, Michael A Seidman, William A Muller","doi":"10.1016/j.ajpath.2025.09.012","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.09.012","url":null,"abstract":"Genetic deletion or antibody blockade of platelet endothelial cell adhesion molecule-1 (CD31, PECAM) inhibits transendothelial migration (TEM) of leukocytes in all mouse strains studied except C57BL/6. A prior publication showed that this phenotype maps to a single 35.8 Mb locus on mouse chromosome 2, that contains the genes Ptgs1, Ptges, and Ptges2, which encode key enzymes involved in the Prostaglandin E2 (PGE2) synthesis pathway. PGE2 is a pro-inflammatory lipid mediator that binds four E prostanoid receptors (EP1-4). It was hypothesized that PGE2 signaling supports TEM via a CD31-independent mechanism. In vitro TEM assays demonstrate that PGE2 or 16,16-dimethyl PGE2 can restore transmigration of polymorphonuclear leukocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) despite a TEM blockade with anti-CD31. This pro-transmigratory effect could be blocked with the EP1 antagonist, SC-51089, or with transient receptor potential canonical 6 (TRPC6) antagonist, BI-749327. 17-phenyl trinor PGE2, an agonist of EP1 and EP3, also restored transmigration of PMNs blocked with anti-CD31. In vivo, PGE2 overcame an anti-CD31 blockade when administered to FVB/n mice in thioglycolate peritonitis or croton oil dermatitis models, whereas blocking EP1 with SC-51089 decreased TEM in C57BL/6 pecam1-/- mice. The findings support earlier data that identified PGE2 as a candidate inducer of CD31-independent TEM, and pinpoint EP1 as the receptor that relays that signal to activate TRPC6.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328146","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

Specialized pro-resolving mediators MaR1 and LXA₄ resolve inflammation during acute chemical lung injury in the absence of neutrophils. 特殊的促溶解介质MaR1和LXA4可在中性粒细胞缺乏的急性化学性肺损伤中缓解炎症。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.013

Maureen E Haynes, Vivienne Fang, Meital Gewirtz, David P Sullivan, William A Muller

{"title":"Specialized pro-resolving mediators MaR1 and LXA4 resolve inflammation during acute chemical lung injury in the absence of neutrophils.","authors":"Maureen E Haynes, Vivienne Fang, Meital Gewirtz, David P Sullivan, William A Muller","doi":"10.1016/j.ajpath.2025.09.013","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.09.013","url":null,"abstract":"Gastric aspiration pneumonia involves chemical injury to the alveoli of the lungs with inflammation, tissue damage, and recruitment of polymorphonuclear leukocytes (PMNs). PMNs are also known to be involved in the production of specialized pro-resolving mediators (SPMs), small lipid molecules that contribute to the resolution of inflammation. This study aimed to identify target PMN-produced SPMs and interrogate their actions and potential use for therapeutic treatment after chemical injury. Our data revealed that Maresin 1 (MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexanoic acid), Lipoxin A4 (LXA4, 5S,6R,15S-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid), and 18-HEPE ((±)-18-hydroxy-5Z,8Z,11Z,14Z,16E-eicosapentaenoic acid) are produced after chemical injury in the lungs, and that exogenous treatment with these SPMs reduces the acute influx of PMNs into the airspace. In a chemical lung injury model in which neutropenic mice all die within 48 hours, treatment with MaR1 or LXA4 rescued survival of neutropenic mice to the levels of immunologically intact mice, and reduced CD11b expression, a pro-inflammatory marker, on recruited PMNs. Exogenous treatment with MaR1 or LXA4 reduced the concentration of pro-inflammatory cytokines TNF⍺, IL6, and MCP-1 in the airspace at 24 h post-injury. These data show that exogenous treatment with MaR1 or LXA4 ameliorates acute inflammation post-chemical lung injury and contributes to survival of severe murine aspiration pneumonia in neutropenic animals. These data have implications for treatment of sterile lung injury in immunocompromised patients.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318084","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

Improving Colorectal Cancer Screening and Risk Assessment through Predictive Modeling on Medical Images and Records. 基于医学影像和记录的预测建模改进结直肠癌筛查和风险评估。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.016

Shuai Jiang, Christina Robinson, Joseph Anderson, William Hisey, Lynn Butterly, Arief Suriawinata, Saeed Hassanpour

{"title":"Improving Colorectal Cancer Screening and Risk Assessment through Predictive Modeling on Medical Images and Records.","authors":"Shuai Jiang, Christina Robinson, Joseph Anderson, William Hisey, Lynn Butterly, Arief Suriawinata, Saeed Hassanpour","doi":"10.1016/j.ajpath.2025.09.016","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.09.016","url":null,"abstract":"Colonoscopy screening effectively identifies and removes polyps before they progress to colorectal cancer (CRC), but current follow-up guidelines rely primarily on histopathological features, overlooking other important CRC risk factors. Variability in polyp characterization among pathologists also hinders consistent surveillance decisions. Advances in digital pathology and deep learning enable the integration of pathology slides and medical records for more accurate progression risk prediction. Using data from the New Hampshire Colonoscopy Registry, including longitudinal follow-up, a transformer-based model for histopathology image analysis was adapted to predict 5-year progression risk. Multi-modal fusion strategies were further explored to combine clinical records with deep learning-derived image features. Training the model to predict intermediate clinical variables improved 5-year progression risk prediction (AUC = 0.630) compared to direct prediction (AUC = 0.615, p = 0.013). Integrating WSI-based model predictions with non-imaging features further improved performance (AUC = 0.672), significantly outperforming the non-imaging-only approach (AUC = 0.666, p = 0.002). These results highlight the value of integrating diverse data modalities with computational methods to enhance progression risk stratification.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318046","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

Inactivation of Atp7b copper transporter in intestinal epithelial cells is associated with altered lipid processing and cell growth machinery independent from hepatic copper accumulation and severity of liver histology. 肠上皮细胞中Atp7b铜转运体的失活与脂质加工和细胞生长机制的改变有关，与肝铜积累和肝脏组织学的严重程度无关。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.015

Amanda Caceres, Noreene M Shibata, Christian D Davalos-Gutierrez, Gaurav V Sarode, Hisham Hussan, Margarida Bettencourt, Adriana Fontes, Hans Zischka, Svetlana Lutsenko, Marie C Heffern, Valentina Medici

{"title":"Inactivation of Atp7b copper transporter in intestinal epithelial cells is associated with altered lipid processing and cell growth machinery independent from hepatic copper accumulation and severity of liver histology.","authors":"Amanda Caceres, Noreene M Shibata, Christian D Davalos-Gutierrez, Gaurav V Sarode, Hisham Hussan, Margarida Bettencourt, Adriana Fontes, Hans Zischka, Svetlana Lutsenko, Marie C Heffern, Valentina Medici","doi":"10.1016/j.ajpath.2025.09.015","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.09.015","url":null,"abstract":"The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and brain, but little is known about the role of other organs expressing the ATP7B copper transporter on metabolic and ultrastructural changes characterizing WD. To examine the consequences of intestinal Atp7b inactivation in the absence of hepatic copper accumulation, a new mouse model (Atp7bΔIEC) characterized by enterocyte-specific Atp7b inactivation was generated. Atp7bΔIEC mice were compared to wildtype mice with the same genetic background (iWT). The Atp7b global knockout (Atp7b-/-) model of WD on a C57Bl/6 background was previously generated and compared to respective WT. Hepatic copper, lipid metabolism, liver and intestine histology and electron microscopy were assessed over time up to 30 weeks of age. Whereas there was no evidence of intestine copper accumulation in the Atp7bΔIEC mice, transcriptome analysis in Atp7bΔIEC mice revealed changes in genes involved in AMPK signaling, fatty acid metabolism, and cell cycle both with partial overlap between the intestinal epithelial cells and the liver. Mitochondrial and other ultrastructural changes were observed in the intestinal epithelial cells of both Atp7b-/- and Atp7bΔIEC mice. Intestine-specific Atp7b deficit affects systemic metabolic pathways and intestine morphology, and hepatic metabolic perturbations are associated with intestinal dysfunction, independently from hepatic copper accumulation, providing evidence that WD phenotype is at least partially influenced by organ-specific ATP7B variants.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318061","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

Transforming Growth Factor-β Signaling in Alcohol-Associated Liver Disease: A Multicellular Perspective. 转化生长因子-β信号在酒精相关肝病中的作用：多细胞视角

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-10-16 DOI: 10.1016/j.ajpath.2025.09.017

Huihui Zou, Sai Wang, Chenjun Huang, Steven Dooley, Nadja M Meindl-Beinker

{"title":"Transforming Growth Factor-β Signaling in Alcohol-Associated Liver Disease: A Multicellular Perspective.","authors":"Huihui Zou, Sai Wang, Chenjun Huang, Steven Dooley, Nadja M Meindl-Beinker","doi":"10.1016/j.ajpath.2025.09.017","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.09.017","url":null,"abstract":"Transforming growth factor-β (TGF-β) signaling exerts broad regulatory n effects on alcohol-associated liver disease (ALD) progression influencing processes such as hepatocellular injury, regeneration, inflammation, fibrogenesis, cirrhosis, carcinogenesis, and hepatic failure. TGF-β modifies alcohol-induced signals in multiple liver-resident cell types, including hepatocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), and immune populations, particularly macrophages. To delinieate its context-specific roles in ALD, 172 of 421 PubMed-listed publications (2000 to 2025, search terms \"TGF-β\" AND \"alcohol\" AND \"liver disease\") were reviewed, supplemented by 18 foundational studies published before. In hepatocytes, TGF-β promotes oxidative stress, apoptosis, metabolic reprogramming, and epithelial-to-mesenchymal transition. In HSCs and Kupffer cells (KCs), gut-derived endotoxins, ethanol, and unsaturated fatty acids induce TGF-β alongside proinflammatory cytokines. Ethanol metabolism generates acetaldehyde, which drives TGF-β and receptor expression, enhances canonical and non-canonical signaling, and engages epigenetic regulators to promote extracellular matrix deposition. In LSECs, alcohol-induced TGF-β suppresses proliferation, contributing to sinusoidal capillarization, impaired endothelial regeneration, and fibrogenesis. TGF-β dampens clearance of damaged hepatocytes and perpetuating chronic injury by suppressing natural killer cell cytotoxicity and promoting regulatory T cell differentiation. At end-stage disease, TGF-β promotes expansion and fate-switching of cholangiocyte-derived liver progenitor cells to replenish lost hepatocytes. Despite its central role in ALD, therapeutic exploitation of TGF-β signaling remains underexplored. Future studies should define cell type-specific signaling nodes to enable precision therapies.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318044","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

Intra-host genomic variation of Haemophilus influenzae isolates from asymptomatic nasopharyngeal carriers involves genes encoding proteins with diverse inferred functions. 从无症状鼻咽病毒携带者分离的流感嗜血杆菌的宿主内基因组变异涉及编码具有多种推断功能的蛋白质的基因。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-10-15 DOI: 10.1016/j.ajpath.2025.09.014

Randall J Olsen, S Wesley Long, Yuvanesh Vedaraju, Sandra Tomasdottir, Helga Erlendsdottir, Ásgeir Haraldsson, Karl G Kristinsson, James M Musser, Gunnsteinn Haraldsson

{"title":"Intra-host genomic variation of Haemophilus influenzae isolates from asymptomatic nasopharyngeal carriers involves genes encoding proteins with diverse inferred functions.","authors":"Randall J Olsen, S Wesley Long, Yuvanesh Vedaraju, Sandra Tomasdottir, Helga Erlendsdottir, Ásgeir Haraldsson, Karl G Kristinsson, James M Musser, Gunnsteinn Haraldsson","doi":"10.1016/j.ajpath.2025.09.014","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.09.014","url":null,"abstract":"Haemophilus influenzae is a human-specific pathogen that causes infections ranging in severity from otitis media to potentially fatal meningitis. It also asymptomatically colonizes the upper respiratory tract. Although intra-host genomic variation of H. influenzae has been investigated in some anatomic sites, the genes most frequently acquiring nonsynonymous (amino acid changing) or nonsense (protein truncating) single nucleotide polymorphisms (SNPs) during human carriage remain largely unidentified. To study intra-host genomic variation of H. influenzae during human asymptomatic carriage in the nasopharynx, the genomes of 805 isolates recovered from 24 healthy Icelandic children were sequenced. Most children were colonized with isolates with a single multilocus sequence type (MLST), although some were concurrently colonized with isolates with multiple MLSTs. Intra-host genomic variation was discovered with 120 genes acquiring SNPs in at least one isolate. Among them, 69 genes were recurrently polymorphic in isolates recovered from multiple children, and 72 SNPs occurred in multiple isolates recovered from the same child. The polymorphic genes encode proteins with diverse inferred functions, including transcription regulators and putative virulence factors. Many of the proteins likely play roles in bacterial fitness, virulence, and host-pathogen molecular interactions. This intra-host variation study provides a model for understanding the genomic diversity acquired by H. influenzae during human asymptomatic carriage in the nasopharynx.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312189","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 : 2025-10-10 DOI: 10.1016/j.ajpath.2025.09.011

引用次数: 0