American Journal of Pathology最新文献

{"title":"Sequential Patching Lattice for Image Classification and Enquiry","authors":"Areej Alsaafin,&nbsp;Peyman Nejat,&nbsp;Abubakr Shafique,&nbsp;Jibran Khan,&nbsp;Saghir Alfasly,&nbsp;Ghazal Alabtah,&nbsp;Hamid R. Tizhoosh","doi":"10.1016/j.ajpath.2024.06.007","DOIUrl":"10.1016/j.ajpath.2024.06.007","url":null,"abstract":"<div><div>Digital pathology and the integration of artificial intelligence (AI) models have revolutionized histopathology, opening new opportunities. With the increasing availability of whole-slide images (WSIs), demand is growing for efficient retrieval, processing, and analysis of relevant images from vast biomedical archives. However, processing WSIs presents challenges due to their large size and content complexity. Full computer digestion of WSIs is impractical, and processing all patches individually is prohibitively expensive. In this article, we propose an unsupervised patching algorithm, Sequential Patching Lattice for Image Classification and Enquiry (SPLICE). This novel approach condenses a histopathology WSI into a compact set of representative patches, forming a collage of WSI while minimizing redundancy. SPLICE prioritizes patch quality and uniqueness by sequentially analyzing a WSI and selecting nonredundant representative features. In search and match applications, SPLICE showed improved accuracy, reduced computation time, and storage requirements compared with existing state-of-the-art methods. As an unsupervised method, SPLICE effectively reduced storage requirements for representing tissue images by 50%. This reduction can enable numerous algorithms in computational pathology to operate much more efficiently, paving the way for accelerated adoption of digital pathology.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1898-1912"},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002384/pdfft?md5=85185165c783af61b921a36727aebaa6&pid=1-s2.0-S0002944024002384-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733316","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":"Single-Nucleus RNA Sequencing Reveals Loss of Distal Convoluted Tubule 1 Renal Tubules in HIV Viral Protein R Transgenic Mice","authors":"Khun Zaw Latt ,&nbsp;Teruhiko Yoshida ,&nbsp;Shashi Shrivastav ,&nbsp;Amin Abedini ,&nbsp;Jeff M. Reece ,&nbsp;Zeguo Sun ,&nbsp;Hewang Lee ,&nbsp;Koji Okamoto ,&nbsp;Pradeep Dagur ,&nbsp;Yu Ishimoto ,&nbsp;Jurgen Heymann ,&nbsp;Yongmei Zhao ,&nbsp;Joon-Yong Chung ,&nbsp;Stephen Hewitt ,&nbsp;Pedro A. Jose ,&nbsp;Kyung Lee ,&nbsp;John Cijiang He ,&nbsp;Cheryl A. Winkler ,&nbsp;Mark A. Knepper ,&nbsp;Tomoshige Kino ,&nbsp;Jeffrey B. Kopp","doi":"10.1016/j.ajpath.2024.06.006","DOIUrl":"10.1016/j.ajpath.2024.06.006","url":null,"abstract":"<div><div>Although hyponatremia and salt wasting are common in patients with HIV/AIDS, the understanding of their contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the distal tubules and on the expression level of the <em>Slc12a3</em> gene, encoding the sodium-chloride cotransporter (which is responsible for sodium reabsorption in distal nephron segments), single-nucleus RNA sequencing was performed on kidney cortices from three wild-type (WT) and three Vpr transgenic (Vpr Tg) mice. The percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (<em>P</em> &lt; 0.05); in Vpr Tg mice, <em>Slc12a3</em> expression was not significantly different in DCT cells. The <em>Pvalb</em>⁺ DCT1 subcluster had fewer cells in Vpr Tg mice compared with those in WT mice (<em>P</em> &lt; 0.01). Immunohistochemistry revealed fewer <em>Slc12a3</em>⁺ <em>Pvalb</em>^<em>+</em> DCT1 segments in Vpr Tg mice. Differential gene expression analysis between Vpr Tg and WT samples in the DCT cluster showed down-regulation of the <em>Ier3</em> gene, which is an inhibitor of apoptosis. The <em>in vitro</em> knockdown of <em>Ier3</em> by siRNA transfection induced apoptosis in mouse DCT cells. These observations suggest that the salt-wasting effect of Vpr in Vpr Tg mice is likely mediated by <em>Ier3</em> down-regulation in DCT1 cells and loss of <em>Slc12a3</em>⁺ <em>Pvalb</em>⁺ DCT1 segments.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1844-1856"},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002372/pdfft?md5=a8ea8d28868ba18519b4cecc36a25926&pid=1-s2.0-S0002944024002372-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733315","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":"The Role of Twist1 in Chronic Pancreatitis–Associated Pancreatic Stellate Cells","authors":"Emma Geister ,&nbsp;Dalton Ard ,&nbsp;Heer Patel ,&nbsp;Alyssa Findley ,&nbsp;Godfrey DeSouza ,&nbsp;Lyndsay Martin ,&nbsp;Henry Knox ,&nbsp;Natasha Gavara ,&nbsp;Aurelia Lugea ,&nbsp;Maria Eugenia Sabbatini","doi":"10.1016/j.ajpath.2024.06.003","DOIUrl":"10.1016/j.ajpath.2024.06.003","url":null,"abstract":"<div><div>In healthy pancreas, pancreatic stellate cells (PaSCs) synthesize the basement membrane, which is mainly composed of type IV collagen and laminin. In chronic pancreatitis (CP), PaSCs are responsible for the production of a rigid extracellular matrix (ECM) that is mainly composed of fibronectin and type I/III collagen. Reactive oxygen species evoke the formation of the rigid ECM by PaSCs. One source of reactive oxygen species is NADPH oxidase (Nox) enzymes. Nox1 up-regulates the expression of Twist1 and matrix metalloproteinase-9 (MMP-9) in PaSCs from mice with CP. This study determined the functional relationship between Twist1 and MMP-9, and other PaSC-produced proteins, and the extent to which Twist1 regulates digestion of ECM proteins in CP. Twist1 induced the expression of MMP-9 in mouse PaSCs. The action of Twist1 was not selective to MMP-9 because Twist1 induced the expression of types I and IV collagen, fibronectin, transforming growth factor, and α-smooth muscle actin. Luciferase assay indicated that Twist1 in human primary PaSCs increased the expression of MMP-9 at the transcriptional level in an NF-κB dependent manner. The digestion of type I/III collagen by MMP-9 secreted by PaSCs from mice with CP depended on Twist1. Thus, Twist1 in PaSCs from mice with CP induced rigid ECM production and MMP-9 transcription in an NF-κB–dependent mechanism that selectively displayed proteolytic activity toward type I/III collagen.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1879-1897"},"PeriodicalIF":4.7,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733317","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.2024.07.001","DOIUrl":"10.1016/j.ajpath.2024.07.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 9","pages":"Page 1607"},"PeriodicalIF":4.7,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002335/pdfft?md5=1b52ea14a6b2b8c06ac4821f96abdafd&pid=1-s2.0-S0002944024002335-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557832","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 Multiscale Connected UNet for the Segmentation of Lung Cancer Cells in Pathology Sections Stained Using Rapid On-Site Cytopathological Evaluation","authors":"","doi":"10.1016/j.ajpath.2024.05.011","DOIUrl":"10.1016/j.ajpath.2024.05.011","url":null,"abstract":"<div><p>Lung cancer is an increasingly serious health problem worldwide, and early detection and diagnosis are crucial for successful treatment. With the development of artificial intelligence and the growth of data volume, machine learning techniques can play a significant role in improving the accuracy of early detection in lung cancer. This study proposes a deep learning-based segmentation algorithm for rapid on-site cytopathological evaluation (ROSE) to enhance the diagnostic efficiency of endobronchial ultrasound-guided transbronchial needle aspiration biopsy (EBUS-TBNA) during surgery. By utilizing the CUNet3+ network model, cell clusters, including cancer cell clusters, can be accurately segmented in ROSE-stained pathological sections. The model demonstrated high accuracy, with an F1-score of 0.9604, recall of 0.9609, precision of 0.9654, and accuracy of 0.9834 on the internal testing data set. It also achieved an area under the receiver-operating characteristic curve of 0.9972 for cancer identification. The proposed algorithm saved time for on-site diagnosis, improved EBUS-TBNA efficiency, and outperformed classical segmentation algorithms in accurately identifying lung cancer cell clusters in ROSE-stained images. It effectively reduced over-segmentation, decreased network parameters, and enhanced computational efficiency, making it suitable for real-time patient evaluation during surgical procedures.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 9","pages":"Pages 1712-1723"},"PeriodicalIF":4.7,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426136","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":"Macrophage Extracellular Traps Suppress Particulate Matter–Induced Airway Inflammation","authors":"","doi":"10.1016/j.ajpath.2024.05.008","DOIUrl":"10.1016/j.ajpath.2024.05.008","url":null,"abstract":"<div><p>Accumulating evidence has substantiated the potential of ambient particulate matter (PM) to elicit detrimental health consequences in the respiratory system, notably airway inflammation. Macrophages, a pivotal component of the innate immune system, assume a crucial function in responding to exogenous agents. However, the roles and detailed mechanisms in regulating PM-induced airway inflammation remain unclear. The current study revealed that PM had the ability to stimulate the formation of macrophage extracellular traps (METs) both <em>in vitro</em> and <em>in vivo</em>. This effect was dependent on peptidylarginine deiminase type 4 (PAD4)–mediated histone citrullination. Additionally, reactive oxygen species were involved in the formation of PM-induced METs, in parallel with PAD4. Genetic deletion of PAD4 in macrophages resulted in an up-regulation of inflammatory cytokine expression. Moreover, mice with PAD4-specific knockout in myeloid cells exhibited exacerbated PM-induced airway inflammation. Mechanistically, inhibition of METs suppressed the phagocytic ability in macrophages, leading to airway epithelial injuries and an aggravated PM-induced airway inflammation. The present study demonstrates that METs play a crucial role in promoting the phagocytosis and clearance of PM by macrophages, thereby suppressing airway inflammation. Furthermore, it suggests that activation of METs may represent a novel therapeutic strategy for PM-related airway disorders.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 9","pages":"Pages 1622-1635"},"PeriodicalIF":4.7,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426137","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":"Bifidobacterium bifidum Strain BB1 Inhibits Tumor Necrosis Factor-α–Induced Increase in Intestinal Epithelial Tight Junction Permeability via Toll-Like Receptor-2/Toll-Like Receptor-6 Receptor Complex–Dependent Stimulation of Peroxisome Proliferator-Activated Receptor γ and Suppression of NF-κB p65","authors":"","doi":"10.1016/j.ajpath.2024.05.012","DOIUrl":"10.1016/j.ajpath.2024.05.012","url":null,"abstract":"<div><p><em>Bifidobacterium bifidum</em> strain BB1 causes a strain-specific enhancement in intestinal epithelial tight junction (TJ) barrier. Tumor necrosis factor (TNF)-α induces an increase in intestinal epithelial TJ permeability and promotes intestinal inflammation. The major purpose of this study was to delineate the protective effect of BB1 against the TNF-α–induced increase in intestinal TJ permeability and to unravel the intracellular mechanisms involved. TNF-α produces an increase in intestinal epithelial TJ permeability in Caco-2 monolayers and in mice. Herein, the addition of BB1 inhibited the TNF-α increase in Caco-2 intestinal TJ permeability and mouse intestinal permeability in a strain-specific manner. BB1 inhibited the TNF-α–induced increase in intestinal TJ permeability by interfering with TNF-α–induced enterocyte NF-κB p50/p65 and myosin light chain kinase (<em>MLCK</em>) gene activation. The BB1 protective effect against the TNF-α–induced increase in intestinal permeability was mediated by toll-like receptor-2/toll-like receptor-6 heterodimer complex activation of peroxisome proliferator-activated receptor γ (PPAR-γ) and PPAR-γ pathway inhibition of TNF-α–induced inhibitory kappa B kinase α (IKK-α) activation, which, in turn, resulted in a step-wise inhibition of NF-κB p50/p65, <em>MLCK</em> gene, MLCK kinase activity, and MLCK-induced opening of the TJ barrier. In conclusion, these studies unraveled novel intracellular mechanisms of BB1 protection against the TNF-α–induced increase in intestinal TJ permeability. The current data show that BB1 protects against the TNF-α–induced increase in intestinal epithelial TJ permeability via a PPAR-γ–dependent inhibition of NF-κB p50/p65 and <em>MLCK</em> gene activation.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 9","pages":"Pages 1664-1683"},"PeriodicalIF":4.7,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002116/pdfft?md5=7b46cac98828e94354d34b70fe195cd8&pid=1-s2.0-S0002944024002116-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141400602","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":"Local Tetanus Begins with a Neuromuscular Junction Paralysis around the Site of Tetanus Neurotoxin Release due to Cleavage of the Vesicle-Associated Membrane Protein","authors":"","doi":"10.1016/j.ajpath.2024.05.009","DOIUrl":"10.1016/j.ajpath.2024.05.009","url":null,"abstract":"<div><p>Local tetanus develops when limited amounts of tetanus neurotoxin (TeNT) are released by <em>Clostridium tetani</em> generated from spores inside a necrotic wound. Within days, a spastic paralysis restricted to the muscles of the affected anatomical area develops. This paralysis follows the retrograde transport of TeNT inside the axons of motoneurons and its uptake by inhibitory interneurons with cleavage of a vesicle-associated membrane protein required for neurotransmitter release. Consequently, incontrollable excitation of motoneurons causes contractures of innervated muscles and leads to local spastic paralysis. Here, the initial events occurring close to the site of TeNT release were investigated in a mouse model of local tetanus. A peripheral flaccid paralysis was found to occur, before or concurrent to the spastic paralysis. At variance from the confined TeNT proteolytic activity taking place within motor neuron terminals, central protein cleavage was detected within inhibitory interneurons controlling motor neuron efferents innervating muscle groups distant from the site of TeNT release. These results indicate peripheral activity of TeNT in tetanus and explains why the spastic paralysis observed in local tetanus, although confined to single limbs, generally affects multiple muscles. The initial TeNT neuroparalytic activity can be detected by measuring the compound muscle action potential, providing a very early diagnosis and therapy, thus preventing the ensuing life-threatening generalized tetanus.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 9","pages":"Pages 1752-1763"},"PeriodicalIF":4.7,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141414307","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":"Platelets in Thrombosis and Atherosclerosis","authors":"","doi":"10.1016/j.ajpath.2024.05.010","DOIUrl":"10.1016/j.ajpath.2024.05.010","url":null,"abstract":"<div><p>This review focuses on the dual role of platelets in atherosclerosis and thrombosis, exploring their involvement in inflammation, angiogenesis, and plaque formation, as well as their hemostatic and prothrombotic functions. Beyond their thrombotic functions, platelets engage in complex interactions with diverse cell types, influencing disease resolution and progression. The contribution of platelet degranulation helps in the formation of atheromatous plaque, whereas the reciprocal interaction with monocytes adds complexity. Alterations in platelet membrane receptors and signaling cascades contribute to advanced atherosclerosis, culminating in atherothrombotic events. Understanding these multifaceted roles of platelets will lead to the development of targeted antiplatelet strategies for effective cardiovascular disease prevention and treatment. Understanding platelet functions in atherosclerosis and atherothrombosis at different stages of disease will be critical for designing targeted treatments and medications to prevent or cure the disease Through this understanding, platelets can be targeted at specific times in the atherosclerosis process, possibly preventing the development of atherothrombosis.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 9","pages":"Pages 1608-1621"},"PeriodicalIF":4.7,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002098/pdfft?md5=d59515c4dc80b0836608c5d9a6b2b766&pid=1-s2.0-S0002944024002098-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141389649","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":"Identification of HTRA4 as a Transcriptional Target of p63 in Trophoblast","authors":"Mary E. Donohoe ,&nbsp;Robert Morey ,&nbsp;Yingchun Li ,&nbsp;Donald Pizzo ,&nbsp;Sampada Kallol ,&nbsp;Hee-Young Cho ,&nbsp;Francesca Soncin ,&nbsp;Mana M. Parast","doi":"10.1016/j.ajpath.2024.03.011","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.03.011","url":null,"abstract":"<div><p>The placenta plays a crucial role in pregnancy success. ΔNp63α (p63), a transcription factor from the TP53 family, is highly expressed in villous cytotrophoblasts (CTBs), the epithelial stem cells of the human placenta, and is involved in CTB maintenance and differentiation. We examined the mechanisms of action of p63 by identifying its downstream targets. Gene expression changes were evaluated following overexpression and knockdown of p63 in the JEG3 choriocarcinoma cell line, using microarray-based RNA profiling. High-temperature requirement A4 (<em>HTRA4</em>), a placenta-specific serine protease involved in trophoblast differentiation and altered in preeclampsia, was identified as a gene reciprocally regulated by p63, and its expression was characterized in primary human placental tissues by RNA-sequencing and <em>in situ</em> hybridization. Potential p63 DNA-binding motifs were identified in the <em>HTRA4</em> promoter, and p63 occupancy at some of these sites was confirmed using chromatin immunoprecipitation, followed by quantitative PCR in both JEG3 and trophoblast stem cells. These data begin to identify members of the transcriptional network downstream of p63, thus laying the groundwork for probing mechanisms by which this important transcription factor regulates trophoblast stemness and differentiation.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 7","pages":"Pages 1162-1170"},"PeriodicalIF":6.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141324427","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}