American Journal of Pathology最新文献

{"title":"Multimodal Diagnostic Imaging of Metabolic Dysfunction–Associated Steatotic Liver Disease","authors":"Alissa Keegan ,&nbsp;Gayathri Malamal ,&nbsp;Yichien Lee ,&nbsp;Kyle Korolowicz ,&nbsp;Blythe D. Shepard ,&nbsp;Carolyn M. Ecelbarger ,&nbsp;Mariana Moya Rubiano ,&nbsp;Maria Laura Avantaggiati ,&nbsp;Moshe Levi ,&nbsp;Laurie Rich ,&nbsp;Massimo Alfano ,&nbsp;Avi Rosenberg ,&nbsp;Stanley Fricke ,&nbsp;Chris Albanese ,&nbsp;Jithin Jose ,&nbsp;Olga Rodriguez","doi":"10.1016/j.ajpath.2025.01.012","DOIUrl":"10.1016/j.ajpath.2025.01.012","url":null,"abstract":"<div><div>Chronic diseases of the liver are major public health concerns worldwide. Steatosis and steatohepatitis associated with alcoholic liver disease, metabolic dysfunction–associated fatty liver disease/nonalcoholic fatty liver disease, and hepatitis B and C contribute to chronic diseases of the liver. Liver fibrosis occurs in all forms of advanced chronic diseases of the liver, the confirmation of which is typically performed by needle biopsy. Imaging approaches for liver diagnosis exist but do not provide sufficient diagnostic accuracy for defining the various stages of fibrosis or steatosis. Therefore, there is a need for improved imaging capabilities to enhance disease diagnosis. Ultrasonography-based photoacoustic imaging has recently emerged as a noninvasive, nonionizing modality, capable of capturing structural details and oxygen saturation changes during disease progression. However, its potential for detecting surrogate metabolic dysfunction–associated fatty liver disease markers, such as collagen and lipids, which are often poorly resolved by other conventional imaging techniques, has yet to be investigated in detail. The novelty of this study lies in the innovative use of spectral photoacoustic imaging for the direct detection and quantification of key biomarkers of liver disease, such as fibrosis, collagen, lipids, and oxygenated and deoxygenated hemoglobin, in a mouse model of steatotic fatty liver disease. Ultrasonography-based photoacoustic imaging, validated with magnetic resonance imaging, effectively identified increases in liver adiposity and fibrosis, enabling the noninvasive detection of changes in liver pathology associated with metabolic dysfunction.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 5","pages":"Pages 875-890"},"PeriodicalIF":4.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424713","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}

{"title":"This Month in AJP","authors":"","doi":"10.1016/j.ajpath.2025.02.001","DOIUrl":"10.1016/j.ajpath.2025.02.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Page 611"},"PeriodicalIF":4.7,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Programmed Death Ligand-1 in Melanoma and Extracellular Vesicles Promotes Local and Regional Immune Suppression through M2-like Macrophage Polarization","authors":"Lili Huang ,&nbsp;Jingbo Yang ,&nbsp;Jinjin Zhu ,&nbsp;Huaishan Wang ,&nbsp;Liyun Dong ,&nbsp;Yeye Guo ,&nbsp;Yeqing Chen ,&nbsp;Feng Zhang ,&nbsp;David J. Xu ,&nbsp;Lingling Ou ,&nbsp;Jaiden R. Xu ,&nbsp;Lei Guan ,&nbsp;Quoc D. Doan ,&nbsp;Andrew Y. Fan ,&nbsp;Wenqun Zhong ,&nbsp;Jina Ko ,&nbsp;Chengyu Liang ,&nbsp;Meenhard Herlyn ,&nbsp;Wei Guo ,&nbsp;Xiaowei Xu ,&nbsp;Shujing Liu","doi":"10.1016/j.ajpath.2024.09.011","DOIUrl":"10.1016/j.ajpath.2024.09.011","url":null,"abstract":"<div><div>Tumor-associated macrophages (TAMs) play dual roles (both pro- and antitumor) in tumor progression. TAMs induce programmed death ligand-1 (PD-L1) expression in cancer cells. However, the regulatory effects of PD-L1 in melanoma cells on TAM phenotypical switching remain underexplored. Herein, <em>CD163</em> and <em>MRC1</em> levels were significantly elevated in metastatic melanomas compared with those in primary melanomas, correlating with <em>CD274</em> expression and predicted patient clinical outcomes. To study the mechanisms regulating M2-like polarization, PD-L1 was knocked out in both YUMM1.7 and B16-F10 melanoma cells. Knocking out PD-L1 (<em>PD-L1</em>^<em>KO</em>) in melanoma resulted in a decelerated <em>in vivo</em> growth rate, accompanied by a significantly increased M1/M2 ratio, more dendritic cells, and enhanced activation of CD8⁺ T cells compared with wild-type (WT) melanoma cells. These alterations were associated with decreased expression of M2-associated chemokines (<em>CCL2</em>, <em>CCL3</em>, and <em>CXCL2</em>) and cytokines (<em>IL6</em>, <em>IL10</em>, and <em>TGF</em><em>B</em><em>1</em>). Mice harboring <em>PD-L1</em>^<em>KO</em> melanomas exhibited elevated levels of CD8⁺ T cells in both the tumor-draining lymph nodes and the bloodstream compared with mice with <em>PD-L1</em>^<em>WT</em> melanomas. Treatment with extracellular vesicles (EVs) derived from <em>PD-L1</em>^<em>KO</em> melanoma resulted in a reduced tumor growth rate and fewer M2-like macrophages in the tumors compared with EVs from <em>PD-L1</em>^<em>WT</em> melanomas. Therefore, these data suggest that PD-L1 in melanoma and melanoma-derived EVs induces M2-like polarization, contributing to local and regional immune suppression.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 306-320"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556934","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}

{"title":"Sphingosine Kinase 2 Controls the Aggressive Phenotype of Oral Squamous Cell Carcinoma by Regulating miR-205 and miR-296 through p53","authors":"Thaís Moré Milan,&nbsp;Gabriel Silva,&nbsp;Lucas Oliveira Sousa,&nbsp;Andréia Machado Leopoldino","doi":"10.1016/j.ajpath.2024.09.009","DOIUrl":"10.1016/j.ajpath.2024.09.009","url":null,"abstract":"<div><div>Alterations in miRNAs, p53, and sphingolipid metabolism are associated with head and neck squamous cell carcinoma (HNSCC). However, the role of sphingosine kinase (SK)-2, an enzyme crucial for sphingolipid metabolism, is poorly understood in HNSCC. The aim of this study was to investigate how SK2 and p53 interact to regulate miRNAs miR-205 and miR-296. Analysis of small-RNA sequencing data from nontumor oral keratinocytes with SK2 overexpression (NOK-SK2) compared to controls (NOK-Ø) revealed differential expression of &gt;100 miRNAs being half-regulated by p53. The expression of miR-205 was down-regulated, and miR-296 was up-regulated, in NOK-SK2 cells; however, cells with SK2 knockdown and p53 overexpression showed an opposite profile. Proteins involved in miRNA biogenesis were increased in NOK-SK2 cells, while levels were decreased in NOK-SK2 cells with p53 overexpression. Transfection with miR-205 mimic and miR-296 inhibitor decreased the aggressiveness and the number of cancer stem-like cells in oral keratinocytes and oral carcinoma cells with SK2 regulation. Overexpression of miR-205 in HN12-SK2 cells decreased tumor-formation capacity, and NOK-SK2 cells abrogated tumor growth in mice. The results indicate crosstalk between SK2 and p53 in regulating miRNAs 205 and 296, which could be potential therapeutic targets in the treatment of HNSCC.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 321-333"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543137","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}

{"title":"Ablation of CD44 Attenuates Adipogenesis in White Adipocytes via the Tryptophan 5-Hydroxylase 2/5-Hydroxytryptamine Axis to Protect Mice from High-Fat Diet–Induced Obesity","authors":"Yuting Wu ,&nbsp;Jinyu Ma ,&nbsp;Jing Chen ,&nbsp;Xiaoyu Liu ,&nbsp;Zhe Wang ,&nbsp;Lan Luo ,&nbsp;Cheng Sun","doi":"10.1016/j.ajpath.2024.10.005","DOIUrl":"10.1016/j.ajpath.2024.10.005","url":null,"abstract":"<div><div>CD44 is a transmembrane protein that plays an essential role in transducing extracellular stimuli into intracellular signaling cascades, especially in cancer cells. Recent studies have shown that CD44 contributes to metabolic regulation. However, the effect of CD44 on adipogenesis in white adipose tissue (WAT) remains unclear. Herein, the expression of CD44 was largely increased in the inguinal and epididymal WAT of obese mice. Ablation or neutralization of CD44 inhibited adipogenesis in cultured adipocytes. CD44-deficient mice were resistant to high-fat diet–induced obesity and metabolic dysfunction. RNA-sequencing, together with functional studies, revealed that reduced expression of tryptophan 5-hydroxylase 2 (<em>Tph2</em>) in WAT was responsible for the repressed adipogenesis in the absence of CD44. The application of 5-hydroxytryptamine, a product of TPH2, rescued the repressed adipogenesis induced by CD44 neutralization. Moreover, the inhibition of TPH2 by p-chlorophenylalanine recapitulated the beneficial phenotypes observed in CD44-deficient mice. Taken together, these data indicate that CD44 plays a pivotal role in adipogenesis in WAT. In this regard, CD44 and its downstream target TPH2 may hold great therapeutic potential for treating excessive adiposity-related metabolic disorders, such as obesity, insulin resistance, and type 2 diabetes.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 247-264"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-Class Segmentation Network Based on Tumor Tissue in Endometrial Cancer Pathology Images","authors":"Tong Yang ,&nbsp;Ping Li ,&nbsp;Bo Liu ,&nbsp;Yuchun Lv ,&nbsp;Dage Fan ,&nbsp;Yuling Fan ,&nbsp;Peizhong Liu ,&nbsp;Yaping Ni","doi":"10.1016/j.ajpath.2024.10.008","DOIUrl":"10.1016/j.ajpath.2024.10.008","url":null,"abstract":"<div><div>Endometrial cancer has the second highest incidence of malignant tumors in the female reproductive system. Accurate and efficient analysis of endometrial cancer pathology images is one of the important research components of computer-aided diagnosis. However, endometrial cancer pathology images have challenges such as smaller solid tumors, lesion areas varying in morphology, and difficulty distinguishing solid and nonsolid tumors, which would affect the accuracy of subsequent pathologic analyses. An Endometrial Cancer Multi-class Transformer Network (ECMTrans-net) is therefore proposed herein to improve the segmentation accuracy of endometrial cancer pathology images. An ECM-Attention module can sequentially infer attention maps along three separate dimensions (channel, local spatial, and global spatial) and multiply the attention maps and the input feature map for adaptive feature refinement. This approach may solve the problems of the small size of solid tumors and similar characteristics of solid tumors to nonsolid tumors and further improve the accuracy of segmentation of solid tumors. In addition, an ECM-Transformer module is proposed, which can fuse multi-class feature information and dynamically adjust the receptive field, solving the issue of complex tumor features. Experiments on the Solid Tumor Endometrial Cancer Pathological (ST-ECP) data set found that performance of the ECMTrans-net was superior to state-of-the-art image segmentation methods, and the average values of accuracy, Mean Intersection over Union, precision, and Dice coefficients were 0.952, 0.927, 0.931, and 0.901, respectively.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 232-246"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543136","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}

{"title":"Segmental Regulation of Intestinal Motility by Colitis and the Adaptive Immune System in the Mouse Ileum and Colon","authors":"Raquel Gomez-Bris ,&nbsp;Pilar Rodríguez-Rodríguez ,&nbsp;Marina Ortega-Zapero ,&nbsp;Santiago Ruvira ,&nbsp;Raquel Castillo-González ,&nbsp;María-Jesús Fernández-Aceñero ,&nbsp;Aránzazu Cruz-Adalia ,&nbsp;Angela Saez ,&nbsp;Silvia-Magdalena Arribas ,&nbsp;Jose-Maria Gonzalez-Granado","doi":"10.1016/j.ajpath.2024.10.020","DOIUrl":"10.1016/j.ajpath.2024.10.020","url":null,"abstract":"<div><div>Gastrointestinal motility disturbances are a hallmark of inflammatory bowel disease (IBD); however, their mechanisms remain unclear. This study used a dextran sulfate sodium–induced colitis mouse model, deficient in mature B and T lymphocytes, to assess intestinal motility and the role of the adaptive immune system in health and IBD. In healthy mice, the absence of adaptive lymphocytes reduced acetylcholine (ACh) sensitivity in the ileum. During colitis, it decreases motility by reducing the intensity and frequency of spontaneous contractions while increasing cholinergic responsiveness. In the proximal colon, adaptive immunity deficiency led to increased contractility and reduced ACh sensitivity in homeostasis, whereas colitis reduced contractile capacity. In the mid colon, immune-deficient mice had reduced ACh sensitivity in homeostasis and exacerbated contractile responses during colitis. In the distal colon, adaptive immunity loss reduced contractility in health and cholinergic responsiveness during colitis. These motility alterations were associated with altered acetylcholinesterase and M2/M3 muscarinic receptor expression. Notably, adaptive lymphocyte deficiency resulted in reduced tissue damage and lower tumor necrosis factor-α expression in the colon during colitis, paralleling intestinal motility changes. Overall, the adaptive immune system critically regulates motility and inflammation across different intestinal segments in IBD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 204-220"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Recognition System for Diagnosing Salivary Gland Neoplasms Based on Vision Transformer","authors":"Mao Li ,&nbsp;Ze-liang Shen ,&nbsp;Hong-chun Xian ,&nbsp;Zhi-jian Zheng ,&nbsp;Zhen-wei Yu ,&nbsp;Xin-hua Liang ,&nbsp;Rui Gao ,&nbsp;Ya-ling Tang ,&nbsp;Zhong Zhang","doi":"10.1016/j.ajpath.2024.09.010","DOIUrl":"10.1016/j.ajpath.2024.09.010","url":null,"abstract":"<div><div>Salivary gland neoplasms (SGNs) represent a group of human neoplasms characterized by a remarkable cytomorphologic diversity, which frequently poses diagnostic challenges. Accurate histologic categorization of salivary gland tumors is crucial to make precise diagnoses and guide decisions regarding patient management. Within the scope of this study, a computer-aided diagnosis model using Vision Transformer (ViT), a cutting-edge deep learning model in computer vision, was developed to accurately classify the most prevalent subtypes of SGNs. These subtypes include pleomorphic adenoma, myoepithelioma, Warthin tumor, basal cell adenoma, oncocytic adenoma, cystadenoma, mucoepidermoid carcinoma, and salivary adenoid cystic carcinoma. The data set comprised 3046 whole slide images of histologically confirmed salivary gland tumors, encompassing nine distinct tissue categories. SGN-ViT exhibited impressive performance in classifying the eight salivary gland tumors, achieving an accuracy of 0.9966, an area under the receiver operating characteristic curve value of 0.9899, precision of 0.9848, recall of 0.9848, and an F1 score of 0.9848. Diagnostic performance of SGN-ViT surpassed that of benchmark models. In a subset of 100 whole slide images, SGN-ViT demonstrated comparable diagnostic performance to that of the chief pathologist while significantly reducing the diagnosis time. These observations indicate that SGN-ViT holds the potential to serve as a valuable computer-aided diagnostic tool for salivary gland tumors, enhancing the diagnostic accuracy of junior pathologists.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 221-231"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567568","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}

{"title":"Evidence and Mechanism of Bile Acid–Mediated Gut-Brain Axis in Anxiety and Depression","authors":"Sydney O. Idahosa ,&nbsp;Rokia Diarra ,&nbsp;Hernoor K. Ranu ,&nbsp;Raidah H. Nasiri ,&nbsp;Sei Higuchi","doi":"10.1016/j.ajpath.2024.10.019","DOIUrl":"10.1016/j.ajpath.2024.10.019","url":null,"abstract":"<div><div>Bidirectional communication between the brain and gastrointestinal tract, called the gut-brain axis, is linked with our emotions. Intestinal lipids, hormones, and molecules, such as bile acids (BAs), impact our mood, motivation, and emotions via the gut-brain axis. BAs are synthesized from cholesterol in the liver and serve as a regulator of lipid metabolism and hormonal secretion in the intestine. Human studies have indicated that the alteration of plasma BA levels is associated with depression and anxiety. Several possible mechanisms, such as BA receptor-dependent and receptor-independent mechanisms, have been reported for emotional control. Animal studies have indicated that the deletion of BA receptors shows behavioral abnormalities. BAs regulate gut hormones, glucagon-like peptide-1 secretion, bioactive lipids, oleoylethanolamide, and the immune system function, which influences neural activities. Thus, BAs act as an emotional regulator. This review aims to summarize the following: clinical evidence of BA concentration linked to mental disorders, including depression and anxiety; and animal studies of BA-related signaling correlated with its neurobehavioral effect supporting its mechanism. We will also discuss future research required for further neurobehavioral treatment.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 163-173"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680643","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}

{"title":"Highlights of the First 100 Years of Publications on Kidney Disease in The American Journal of Pathology","authors":"Michael S. Goligorsky","doi":"10.1016/j.ajpath.2024.11.001","DOIUrl":"10.1016/j.ajpath.2024.11.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 2","pages":"Pages 158-162"},"PeriodicalIF":4.7,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045579","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}