Laboratory Investigation最新文献

{"title":"Pathogenic Roles for RNASET2 in Clear Cell Renal Cell Carcinoma","authors":"Taylor Peak ,&nbsp;Yijun Tian ,&nbsp;Aman Patel ,&nbsp;Tim Shaw ,&nbsp;Alyssa Obermayer ,&nbsp;Jose Laborde ,&nbsp;Youngchul Kim ,&nbsp;Joseph Johnson ,&nbsp;Paul Stewart ,&nbsp;Bin Fang ,&nbsp;Jamie K. Teer ,&nbsp;John Koomen ,&nbsp;Anders Berglund ,&nbsp;Doug Marchion ,&nbsp;Natasha Francis ,&nbsp;Paola Ramos Echevarria ,&nbsp;Jasreman Dhillon ,&nbsp;Noel Clark ,&nbsp;Andrew Chang ,&nbsp;Wade Sexton ,&nbsp;Brandon Manley","doi":"10.1016/j.labinv.2024.102041","DOIUrl":"10.1016/j.labinv.2024.102041","url":null,"abstract":"<div><p>A specific splicing isoform of <em>RNASET2</em> is associated with worse oncologic outcomes in clear cell renal cell carcinoma (ccRCC). However, the interplay between wild-type RNASET2 and its splice variant and how this might contribute to the pathogenesis of ccRCC remains poorly understood. We sought to better understand the relationship of RNASET2 in the pathogenesis of ccRCC and the interplay with a pathogenic splicing isoform (<em>RNASET2</em>-SV) and the tumor immune microenvironment. Using data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium, we correlated clinical variables to RNASET2 expression and the presence of a specific RNASET2-SV. Immunohistochemical staining with matched RNA sequencing of ccRCC patients was then utilized to understand the spatial relationships of RNASET2 with immune cells. Finally, in vitro studies were performed to demonstrate the oncogenic role of RNASET2 and highlight its potential mechanisms<em>. RNASET2</em> gene expression is associated with higher grade tumors and worse overall survival in The Cancer Genome Atlas cohort. The presence of the <em>RNASET2</em>-SV was associated with increased expression of the wild-type RNASET2 protein and epigenetic modifications of the gene. Immunohistochemical staining revealed increased intracellular accumulation of RNASET2 in patients with increased RNA expression of <em>RNASET2</em>-SV. In vitro experiments reveal that this accumulation results in increased cell proliferation, potentially from altered metabolic pathways. RNASET2 exhibits a tumor-promoting role in the pathogenesis of ccRCC that is increased in the presence of a specific <em>RNASET2</em>-SV and associated with changes in the cellular localization of the protein.</p></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140022149","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":"Advancing Artificial Intelligence Integration Into the Pathology Workflow: Exploring Opportunities in Gastrointestinal Tract Biopsies","authors":"Fazilet Yilmaz ,&nbsp;Arlen Brickman ,&nbsp;Fedaa Najdawi ,&nbsp;Evgeny Yakirevich ,&nbsp;Robert Egger ,&nbsp;Murray B. Resnick","doi":"10.1016/j.labinv.2024.102043","DOIUrl":"10.1016/j.labinv.2024.102043","url":null,"abstract":"<div><p>This review aims to present a comprehensive overview of the current landscape of artificial intelligence (AI) applications in the analysis of tubular gastrointestinal biopsies. These publications cover a spectrum of conditions, ranging from inflammatory ailments to malignancies. Moving beyond the conventional diagnosis based on hematoxylin and eosin–stained whole-slide images, the review explores additional implications of AI, including its involvement in interpreting immunohistochemical results, molecular subtyping, and the identification of cellular spatial biomarkers. Furthermore, the review examines how AI can contribute to enhancing the quality and control of diagnostic processes, introducing new workflow options, and addressing the limitations and caveats associated with current AI platforms in this context.</p></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140022147","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":"Proteomic Profiles of Human Arterioles Isolated From Fresh Adipose Tissue or Following Overnight Storage","authors":"Rajan Pandey ,&nbsp;Michelle L. Roberts ,&nbsp;Jingli Wang ,&nbsp;Michaela Pereckas ,&nbsp;David Jensen ,&nbsp;Andrew S. Greene ,&nbsp;Michael E. Widlansky ,&nbsp;Mingyu Liang","doi":"10.1016/j.labinv.2024.102036","DOIUrl":"10.1016/j.labinv.2024.102036","url":null,"abstract":"<div><p>Arterioles are key determinants of the total peripheral vascular resistance, which, in turn, is a key determinant of arterial blood pressure. However, the amount of protein available from one isolated human arteriole may be less than 5 μg, making proteomic analysis challenging. In addition, obtaining human arterioles requires manual dissection of unfrozen clinical specimens. This limits its feasibility, especially for powerful multicenter clinical studies in which clinical specimens need to be shipped overnight to a research laboratory for arteriole isolation. We performed a study to address low-input, test overnight tissue storage and develop a reference human arteriolar proteomic profile. In tandem mass tag proteomics, use of a booster channel consisting of human induced pluripotent stem cell–derived endothelial and vascular smooth muscle cells (1:5 ratio) increased the number of proteins detected in a human arteriole segment with a false discovery rate of &lt;0.01 from 1051 to more than 3000. The correlation coefficient of proteomic profile was similar between replicate arterioles isolated freshly, following cold storage, or before and after the cold storage (1-way analysis of variance; <em>P</em> = .60). We built a human arteriolar proteomic profile consisting of 3832 proteins based on the analysis of 12 arteriole samples from 3 subjects. Of 1945 blood pressure–relevant proteins that we curated, 476 (12.5%) were detected in the arteriolar proteome, which was a significant overrepresentation (χ² test; <em>P</em> &lt; .05). These findings demonstrate that proteomic analysis is feasible with arterioles isolated from human adipose tissue following cold overnight storage and provide a reference human arteriolar proteome profile highly valuable for studies of arteriole-related traits.</p></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975483","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":"Indolent T-Cell/Natural Killer-Cell Lymphomas/Lymphoproliferative Disorders of the Gastrointestinal Tract—What Have We Learned in the Last Decade?","authors":"Xin-Gen Wang ,&nbsp;Wei-Hua Yin ,&nbsp;Huan-You Wang","doi":"10.1016/j.labinv.2024.102028","DOIUrl":"10.1016/j.labinv.2024.102028","url":null,"abstract":"<div><p>Primary gastrointestinal (GI) T-cell and natural killer (NK)–cell lymphomas/lymphoproliferative disorders (LPD) are uncommon, and they are usually aggressive in nature. However, T-cell and NK-cell lymphoma/LPD of the GI tract with indolent clinical course has been reported over the past 2 decades. Indolent T-cell LPD was formally proposed a decade ago in 2013 and 4 years later recognized as a provisional entity by the revised fourth edition of <em>WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues</em> in 2017. Indolent T-cell LPD of the GI tract has been changed to indolent T-cell lymphoma of the GI tract as a distinct entity by the fifth edition of <em>WHO Classification of Haematolymphoid Tumours</em>, but the International Consensus Classification of mature lymphoid neoplasms prefers indolent clonal T-cell LPD of the GI tract instead. In the past decade, indolent lymphoma/LPD of the GI tract has been expanded to NK cells, and as such, indolent NK-cell LPD of the GI tract was recognized as an entity by both the fifth edition of <em>WHO Classification of Haematolymphoid Tumours</em> and the International Consensus Classification. The underlying genetic/molecular mechanisms of both indolent T-cell lymphoma/LPD of the GI tract and indolent NK-cell LPD of the GI tract have been recently discovered. In this review, we describe the history; salient clinical, cytohistomorphologic, and immunohistochemical features; and genetic/genomic landscape of both entities. In addition, we also summarize the mimics and differential diagnosis. Finally, we propose future directions with regard to the pathogenesis and clinical management.</p></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139931792","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":"Mediation of Ferroptosis Suppressor Protein 1 Expression via 4-Hydroxy-2-Nonenal Accumulation Contributes to Acquisition of Resistance to Apoptosis and Ferroptosis in Diffuse Large B-Cell Lymphoma","authors":"Genji Kawade ,&nbsp;Morito Kurata ,&nbsp;Yuko Matsuki ,&nbsp;Sho Fukuda ,&nbsp;Iichiroh Onishi ,&nbsp;Yuko Kinowaki ,&nbsp;Shiori Watabe ,&nbsp;Sachiko Ishibashi ,&nbsp;Masumi Ikeda ,&nbsp;Masahide Yamamoto ,&nbsp;Kenichi Ohashi ,&nbsp;Masanobu Kitagawa ,&nbsp;Kouhei Yamamoto","doi":"10.1016/j.labinv.2024.102027","DOIUrl":"10.1016/j.labinv.2024.102027","url":null,"abstract":"<div><p>Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. New therapeutic strategies are needed for the treatment of refractory DLBCL. 4-Hydroxy-2-nonenal (4-HNE) is a cytotoxic lipid peroxidation marker, which alters intracellular signaling and induces genetic mutations. Lipid peroxidation is associated with nonapoptotic cell death, called ferroptosis. However, the relationship between 4-HNE accumulation and feroptotic regulators in DLBCL has not been fully evaluated. Here, we aimed to evaluate the accumulation of lipid peroxide and the expression of ferroptosis suppressor protein 1 (FSP1) in DLBCL using immunohistochemistry. We found a significant increase in the expression of FSP1 in cases with nuclear 4-HNE accumulation (<em>P</em> = .021). Both nuclear and cytoplasmic 4-HNE accumulation and FSP1 positivity were independent predictors of worse prognosis. In vitro exposure to 4-HNE resulted in its concentration- and time-dependent intracellular accumulation and increased expression of FSP1. Furthermore, short-term (0.25 and 1.0 μM) or long-term (0.25 μM) exposure to 4-HNE induced resistance to not only apoptosis but also ferroptosis. Taken together, regulation of FSP1 through 4-HNE accumulation may attenuate resistance to cell death in treatment-resistant DLBCL and might help develop novel therapeutic strategies for refractory DLBCL.</p></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139681290","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":"PI3Kδ Mediates Fibrosis by Patient-Derived Vitreous","authors":"Dan Liu ,&nbsp;Bin Yan ,&nbsp;Yiwei Yin ,&nbsp;Fang Chen ,&nbsp;Cao Guo ,&nbsp;Qin Li ,&nbsp;Jia Liu ,&nbsp;Li Pu ,&nbsp;Wenyi Wu ,&nbsp;Jing Luo","doi":"10.1016/j.labinv.2024.102026","DOIUrl":"10.1016/j.labinv.2024.102026","url":null,"abstract":"<div><p>The epithelial-mesenchymal transition (EMT) is a fundamental process in developing fibrotic diseases, including forming epiretinal membranes (ERMs). ERMs can result in irreversible vision loss. Previous research has demonstrated that vitreous (VIT) derived from patients with proliferative diabetic retinopathy can stimulate angiogenesis through the Axl/PI3K/Akt pathway. Building upon this knowledge, we aimed to explore the influence of VIT from patients with macular membranes in ARPE-19 cells. Our findings reveal that patient-derived VIT from individuals with macular membranes promotes EMT and phosphoinositide 3-kinase-delta (PI3Kδ) expression in ARPE-19 cells. To elucidate the function of PI3Kδ in the ERM, we conducted experiments involving the knockout of p110δ, a key subunit of PI3Kδ, and observed that its absence hinders EMT induced by patient-derived VIT. Moreover, p110δ depletion reduces cell proliferation and migration in ARPE-19 cells. Remarkably, these effects were further corroborated by applying the p110δ inhibitor idelalisib, which blocks fibrosis in the laser-induced fibrosis model. Collectively, our results propose that p110δ plays a critical role in the progression of ERMs. Consequently, targeting p110δ emerges as a promising therapeutic approach for mitigating fibrosis. These findings contribute to a better understanding of the underlying mechanisms involved in ERM formation and highlight the potential for p110δ-directed antifibrotic therapy in retinal diseases.</p></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139672139","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":"Influence of Growth Differentiation Factor 15 on Intraocular Pressure in Mice","authors":"Rupalatha Maddala ,&nbsp;Camelia Eldawy ,&nbsp;Leona T.Y. Ho ,&nbsp;Pratap Challa ,&nbsp;Ponugoti V. Rao","doi":"10.1016/j.labinv.2024.102025","DOIUrl":"10.1016/j.labinv.2024.102025","url":null,"abstract":"<div><p>Growth differentiation factor 15 (GDF15), a stress-sensitive cytokine, and a distant member of the transforming growth factor β superfamily, has been shown to exhibit increased levels with aging, and in various age-related pathologies. Although GDF15 levels are elevated in the aqueous humor (AH) of glaucoma (optic nerve atrophy) patients, the possible role of this cytokine in the modulation of intraocular pressure (IOP) or AH outflow is unknown. The current study addresses this question using transgenic mice expressing human GDF15 and GDF15 null mice, and by perfusing enucleated mouse eyes with recombinant human GDF15 (rhGDF15). Treatment of primary cultures of human trabecular meshwork cells with a telomerase inhibitor, an endoplasmic reticulum stress–inducing agent, hydrogen peroxide, or an autophagy inhibitor resulted in significant elevation in GDF15 levels relative to the respective control cells. rhGDF15 stimulated modest but significant increases in the expression of genes encoding the extracellular matrix, cell adhesion proteins, and chemokine receptors (C-C chemokine receptor type 2) in human trabecular meshwork cells compared with controls, as deduced from the differential transcriptional profiles using RNA-sequencing analysis. There was a significant increase in IOP in transgenic mice expressing human GDF15, but not in GDF15 null mice, compared with the respective wild-type control mice. The AH outflow facility was decreased in enucleated wild-type mouse eyes perfused with rhGDF15. Light microcopy–based histologic examination of the conventional AH outflow pathway tissues did not reveal identifiable differences between the GDF15-targeted and control mice. Taken together, these results reveal the modest elevation of IOP in mice expressing human GDF15 possibly stemming from decreased AH outflow through the trabecular pathway.</p></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642496","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":"Reliability and Variability of Ki-67 Digital Image Analysis Methods for Clinical Diagnostics in Breast Cancer","authors":"Melanie Dawe ,&nbsp;Wei Shi ,&nbsp;Tian Y. Liu ,&nbsp;Katherine Lajkosz ,&nbsp;Yukiko Shibahara ,&nbsp;Nakita E.K. Gopal ,&nbsp;Rokshana Geread ,&nbsp;Seyed Mirjahanmardi ,&nbsp;Carrie X. Wei ,&nbsp;Sehrish Butt ,&nbsp;Moustafa Abdalla ,&nbsp;Sabrina Manolescu ,&nbsp;Sheng-Ben Liang ,&nbsp;Dianne Chadwick ,&nbsp;Michael H.A. Roehrl ,&nbsp;Trevor D. McKee ,&nbsp;Adewunmi Adeoye ,&nbsp;David McCready ,&nbsp;April Khademi ,&nbsp;Fei-Fei Liu ,&nbsp;Susan J. Done","doi":"10.1016/j.labinv.2024.100341","DOIUrl":"10.1016/j.labinv.2024.100341","url":null,"abstract":"<div><p>Ki-67 is a nuclear protein associated with proliferation, and a strong potential biomarker in breast cancer, but is not routinely measured in current clinical management owing to a lack of standardization. Digital image analysis (DIA) is a promising technology that could allow high-throughput analysis and standardization. There is a dearth of data on the clinical reliability as well as intra- and interalgorithmic variability of different DIA methods. In this study, we scored and compared a set of breast cancer cases in which manually counted Ki-67 has already been demonstrated to have prognostic value (n = 278) to 5 DIA methods, namely Aperio ePathology (Lieca Biosystems), Definiens Tissue Studio (Definiens AG), Qupath, an unsupervised immunohistochemical color histogram algorithm, and a deep-learning pipeline piNET. The piNET system achieved high agreement (interclass correlation coefficient: 0.850) and correlation (R = 0.85) with the reference score. The Qupath algorithm exhibited a high degree of reproducibility among all rater instances (interclass correlation coefficient: 0.889). Although piNET performed well against absolute manual counts, none of the tested DIA methods classified common Ki-67 cutoffs with high agreement or reached the clinically relevant Cohen’s κ of at least 0.8. The highest agreement achieved was a Cohen’s κ statistic of 0.73 for cutoffs 20% and 25% by the piNET system. The main contributors to interalgorithmic variation and poor cutoff characterization included heterogeneous tumor biology, varying algorithm implementation, and setting assignments. It appears that image segmentation is the primary explanation for semiautomated intra-algorithmic variation, which involves significant manual intervention to correct. Automated pipelines, such as piNET, may be crucial in developing robust and reproducible unbiased DIA approaches to accurately quantify Ki-67 for clinical diagnosis in the future.</p></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0023683724000199/pdfft?md5=a56a6fae2b900e1346e39173fd7e4a6f&pid=1-s2.0-S0023683724000199-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139570542","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":"Bile Acid Receptor Agonist Reverses Transforming Growth Factor-β1–Mediated Fibrogenesis in Human Induced Pluripotent Stem Cells–Derived Kidney Organoids","authors":"Xiaoping Yang ,&nbsp;Marco Delsante ,&nbsp;Parnaz Daneshpajouhnejad ,&nbsp;Paride Fenaroli ,&nbsp;Kira Perzel Mandell ,&nbsp;Xiaoxin Wang ,&nbsp;Shogo Takahashi ,&nbsp;Marc K. Halushka ,&nbsp;Jeffrey B. Kopp ,&nbsp;Moshe Levi ,&nbsp;Avi Z. Rosenberg","doi":"10.1016/j.labinv.2024.100336","DOIUrl":"10.1016/j.labinv.2024.100336","url":null,"abstract":"<div><p>Chronic kidney disease progresses through the replacement of functional tissue compartments with fibrosis, a maladaptive repair process. Shifting kidney repair toward a physiologically intact architecture, rather than fibrosis, is key to blocking chronic kidney disease progression. Much research into the mechanisms of fibrosis is performed in rodent models with less attention to the human genetic context. Recently, human induced pluripotent stem cell (iPSC)-derived organoids have shown promise in overcoming the limitation. In this study, we developed a fibrosis model that uses human iPSC-based 3-dimensional renal organoids, in which exogenous transforming growth factor-β1 (TGF-β1) induced the production of extracellular matrix. TGF-β1-treated organoids showed tubulocentric collagen 1α1 production by regulating downstream transcriptional regulators, Farnesoid X receptor, phosphorylated mothers against decapentaplegic homolog 3 (p-SMAD3), and <em>t</em>ranscriptional co<em>a</em>ctivator with PD<em>Z</em>-binding motif (TAZ). Increased nuclear <em>TAZ</em> expression was confirmed in the tubular epithelium in human kidney biopsies with tubular injury and early fibrosis. A dual bile acid receptor agonist (INT-767) increased Farnesoid X receptor and reduced p-SMAD3 and TAZ, attenuating TGF-β1-induced fibrosis in kidney organoids. Finally, we show that TAZ interacted with TEA-domain transcription factors and p-SMAD3 with TAZ and TEA-domain transcription factor 4 coregulating <em>collagen 1α1</em> gene transcription. In summary, we establish a novel, readily manipulable fibrogenesis model and posit a role for bile acid receptor agonism early in renal parenchymal fibrosis.</p></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139546772","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":"Gasdermin D-Mediated Pyroptosis Promotes the Development of Atherosclerosis","authors":"Bangbang Huang ,&nbsp;Zhenhuan Zou ,&nbsp;Yinshuang Li ,&nbsp;Hui Chen ,&nbsp;Kunmei Lai ,&nbsp;Ying Yuan ,&nbsp;Yanfang Xu","doi":"10.1016/j.labinv.2024.100337","DOIUrl":"10.1016/j.labinv.2024.100337","url":null,"abstract":"<div><p>Atherosclerosis is a chronic inflammatory cardiovascular disease with a high-morbidity and mortality rate. An increasing number of studies have addressed the crucial contribution of gasdermin D (GSDMD)-mediated pyroptosis, which is triggered by the inflammasomes to the development of atherosclerosis. However, the underlying mechanism is still unclear. This study aimed to uncover the detailed role of GSDMD in the development of atherosclerosis. An atherosclerotic model was established in <em>Gsdmd</em>^<em>-/-</em><em>/Ldlr</em>^<em>-/-</em> mice and <em>Gsdmd</em>^<em>+/+</em><em>/Ldlr</em>^<em>-/-</em> mice fed with a high-fat diet. The atherosclerotic lesions, the activation of GSDMD, and the expression level of inflammatory cytokines and chemokines were evaluated. <em>Gsdmd</em> deletion ameliorated the atherosclerotic lesion sizes and the infiltration of immune cells and inflammatory cells in the aortas of mice. Additionally, <em>Gsdmd</em> deletion suppressed the pyroptosis of macrophages and endothelial cells induced by the serum of <em>Ldlr</em>^<em>-/-</em> mice fed with a high-fat diet. Furthermore, the formation of neutrophil extracellular traps was also attenuated by knockout of <em>Gsdmd</em>. Bone marrow chimeras confirmed that the genetic deficiency of <em>Gsdmd</em> in both immune cells and intrinsic cells played a role in the promotion of arteriosclerosis. Collectively, our study demonstrated that <em>Gsdmd</em> deletion hindered the pathogenesis of atherosclerosis by inhibiting endothelial cell and macrophage cell death, and the formation of neutrophil extracellular traps.</p></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139546775","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}