American Journal of Pathology最新文献

{"title":"Medulloblastomas Initiated by Homologous Recombination Defects in Mice","authors":"Huimei Lu ,&nbsp;Yuan Wang ,&nbsp;Shipra Chaudhary ,&nbsp;Varshita Balaga ,&nbsp;Hua Ke ,&nbsp;Fuqian Shi ,&nbsp;Jingmei Liu ,&nbsp;Yanying Huo ,&nbsp;Peter J. Romanienko ,&nbsp;Bing Xia ,&nbsp;Subhajyoti De ,&nbsp;Chang S. Chan ,&nbsp;Zhiyuan Shen","doi":"10.1016/j.ajpath.2024.07.018","DOIUrl":"10.1016/j.ajpath.2024.07.018","url":null,"abstract":"<div><div>Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibit genomic signatures of HR defects. Whether ablation of <em>Brca2</em> and <em>Palb2</em>, and their related <em>Brca1</em> and <em>Bccip</em> genes, in the mouse brain can differentially initiate medulloblastomas was explored here. Conditional knockout mouse models of these HR genes and a conditional knockdown of <em>Bccip</em> (<em>shBccip-KD</em>) were established. Deletion of any of these genes led to microcephaly and neurologic defects, with <em>Brca1</em>^<em>–</em> and <em>Bccip</em>^<em>–</em> producing the worst defects. <em>Trp53</em> co-deletion significantly rescued the microcephaly with <em>Brca1</em>, <em>Palb2</em>, and <em>Brca2</em> deficiency but exhibited limited impact on <em>Bccip</em>^– mice. For the first time, inactivation of either <em>Brca1</em> or <em>Palb2</em> with <em>Trp53</em> was found to induce medulloblastomas. Despite <em>shBccip-CKD</em> being highly penetrative, <em>Bccip/Trp53</em> deletions failed to induce medulloblastomas. The tumors displayed diverse immunohistochemical features and chromosome copy number variation. Although there were widespread up-regulations of cell proliferative pathways, most of the tumors expressed biomarkers of the sonic hedgehog subgroup. The medulloblastomas developed from <em>Brca1</em>^<em>–</em><em>, Palb2</em>^<em>–</em><em>,</em> and <em>Brca2</em>^– mice were highly sensitive to a poly (ADP-ribose) polymerase inhibitor but not the ones from <em>shBccip-CKD</em> mice. These models recapitulate the spontaneous medulloblastoma development with high penetrance and a narrow time window, providing ideal platforms to test therapeutic agents with the ability to differentiate HR-defective and HR-proficient tumors.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2007-2022"},"PeriodicalIF":4.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016037","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":"TRIM24 Up-Regulates ORM2 to Alleviate Abnormal Lipid Metabolism, Inflammation, and Oxidative Stress in Mice with Obstructive Sleep Apnea Syndrome and Metabolic Dysfunction–Associated Steatotic Liver Disease","authors":"Hui Zhang ,&nbsp;Si Lei ,&nbsp;Hui Zhuo ,&nbsp;Yan Xu ,&nbsp;Yun Ye ,&nbsp;Yingquan Luo","doi":"10.1016/j.ajpath.2024.07.020","DOIUrl":"10.1016/j.ajpath.2024.07.020","url":null,"abstract":"<div><div>Obstructive sleep apnea syndrome (OSAS) is associated with the development and progression of metabolic dysfunction–associated steatotic liver disease (MASLD). Tripartite motif containing 24 (<em>TRIM24</em>) deficiency causes hepatic lipid accumulation and hepatitis. However, the expression, function, and mechanism of <em>TRIM24</em> in OSAS and MASLD remain unclear. Herein, an OSAS and MASLD mouse model was established by intermittent hypoxia (IH) and high-fat diet. IH- and 1% free fatty acid–induced mouse liver cells served as an <em>in vitro</em> model. <em>TRIM24</em> and <em>HIF1A</em> were up-regulated under the IH condition. <em>HIF1A</em> enhanced the transcriptional activity of <em>TRIM24</em>. Overexpression of <em>TRIM24</em> reduced hepatic lipid accumulation, decreased serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol, and increased serum levels of high-density lipoprotein cholesterol in OSAS and MASLD mice. Additionally, overexpression of <em>TRIM24</em> alleviated inflammation and oxidative stress, and modulated aberrant lipid metabolism. Mechanically, <em>TRIM24</em> up-regulated the expression of <em>ORM2</em>, a key regulator of hepatic lipogenesis, by binding to H3K27ac and recruiting retinoic acid receptor-α to <em>ORM2</em> promoter. The cell rescue model was used to verify that <em>ORM2</em> mediated the hepatoprotective effects of <em>TRIM24</em>. The current study reveals the important role of <em>TRIM24</em> as an epigenetic coregulator of transcription in OSAS and MASLD, providing additional insights into understanding the pathogenesis and preventing the development of OSAS and MASLD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2091-2105"},"PeriodicalIF":4.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016038","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":"Immunoregulatory Properties of Immune Cells that Associate with the Lens Capsule Surface during Acute and Resolution Phases of Experimental Autoimmune Uveitis","authors":"Phuong M. Le ,&nbsp;Mary J. Mattapallil ,&nbsp;Rachel R. Caspi ,&nbsp;Mary Ann Stepp ,&nbsp;A. Sue Menko","doi":"10.1016/j.ajpath.2024.07.021","DOIUrl":"10.1016/j.ajpath.2024.07.021","url":null,"abstract":"<div><div>Inflammation in the eye is tightly regulated to prevent vision impairment and irreversible blindness. Emerging evidence shows that immune cells are specifically recruited to the lens capsule in response to autoimmune uveitis, yet the potential that they have a role in regulating this inflammatory disease remained unexplored. Here, an immunolocalization approach combined with high-resolution confocal microscopy was used to investigate whether the immune cells that become stably associated with the lens capsule in the eyes of C57BL/6J mice with experimental autoimmune uveitis (EAU) have an immunoregulatory phenotype. These studies revealed that during the acute phase of uveitis, at day 18 after disease induction, the immune cells specifically recruited to the lens capsule, such as regulatory T cells [forkhead box P3 (FoxP3)⁺CD4⁺] and M2 macrophages (CD68⁺ arginase 1⁺IL-10⁺), included those with putative anti-inflammatory, proresolution roles. The frequency of these lens capsule–associated immunomodulatory phenotypes increased at day 35 after induction, during the resolution phase of EAU inflammation. At this later stage of resolution, most of the macrophages expressed CD206, a mannose receptor responsible for removing inflammatory molecules, in addition to arginase 1 and IL-10. These results suggest a previously unknown role for the lens as a site for recruitment of immune cells whose role is to suppress inflammation, promote resolution, and maintain remission of EAU.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2194-2211"},"PeriodicalIF":4.7,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003414","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 Circadian Clock of Müller Glia Is Necessary for Retinal Homeostasis and Neuronal Survival","authors":"Lauren Pickel ,&nbsp;Soo Jin Kim ,&nbsp;Sabiha Hacibekiroglu ,&nbsp;Andras Nagy ,&nbsp;Junyeop Lee ,&nbsp;Hoon-Ki Sung","doi":"10.1016/j.ajpath.2024.07.017","DOIUrl":"10.1016/j.ajpath.2024.07.017","url":null,"abstract":"<div><div>Biological processes throughout the body are orchestrated in time through the regulation of local circadian clocks. The retina is among the most metabolically active tissues, with demands depending greatly on the light/dark cycle. Most cell types within the rodent retina are known to express the circadian clock; however, retinal clock expression in humans has not previously been localized. Moreover, the effect of local circadian clock dysfunction on retinal homeostasis is incompletely understood. The current study indicated an age-dependent decline in circadian clock gene and protein expression in the human retina. An animal model of targeted <em>Bmal1</em> deficiency was used to identify the circadian clock of the retinal Müller glia as essential for neuronal survival, vascular integrity, and retinal function. These results suggest a potential role for the local retinal circadian clock within the Müller glia in age-related retinal disease and retinal degeneration.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2179-2193"},"PeriodicalIF":4.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987247","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":"Intestinal Dysbacteriosis Contributes to Persistent Cognitive Impairment after Resolution of Acute Liver Failure","authors":"Zhen Li ,&nbsp;Tianning Sun ,&nbsp;Zhigang He ,&nbsp;Zhixiao Li ,&nbsp;Jun Xiong ,&nbsp;Hongbing Xiang","doi":"10.1016/j.ajpath.2024.07.014","DOIUrl":"10.1016/j.ajpath.2024.07.014","url":null,"abstract":"<div><div>Regulating the gut microbiota alleviates hepatic encephalopathy (HE). Whether it is imperative to withhold treatment for microbial imbalance after liver functional recovery remains unclear. The aim of this work was to elucidate the alterations in cognitive behavior, liver function, synaptic transmission, and brain metabolites in acute liver failure (ALF) mice before and after hepatic function recovery. Towards this end, thioacetamide was injected intraperitoneally to establish an ALF mouse model, which induced HE. Hierarchical clustering analysis indicated that while the liver functions normalized, cognitive dysfunction and intestinal dysbacteriosis occurred in the ALF mice 14 days after thioacetamide injection. In addition, fecal microbiota transplantation from the ALF mice with liver function recovery induced liver injury and cognitive impairment. Alterations in synaptic transmission were found in the ALF mice with liver function improvement, and the correlations between the gut bacteria and synaptic transmission in the cortex were significant. Finally, apparent alterations in the brain metabolic profiles of the ALF mice were detected after liver function improvement by performing ¹H nuclear magnetic resonance spectroscopy, suggesting a risk of HE. These results showed that intestinal dysbacteriosis in ALF mice with liver function recovery is sufficient to induce liver injury and cognitive impairment. This indicates that continuous care may be necessary for monitoring microbial imbalance even in patients with ALF-induced HE whose liver function has recovered significantly.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2076-2090"},"PeriodicalIF":4.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987246","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":"Differential Abundance of DNA Damage Sensors and Innate Immune Signaling Proteins in Inositol Polyphosphate 4-Phosphatase Type II–Negative Triple-Negative Breast Cancer Classified by Immunotype","authors":"F. Scott Heinemann ,&nbsp;Paul D. Gershon","doi":"10.1016/j.ajpath.2024.07.015","DOIUrl":"10.1016/j.ajpath.2024.07.015","url":null,"abstract":"<div><div>The influence of neoplastic cells on the tumor microenvironment is poorly understood. In this study, eight patient samples representing two immunotypes of triple-negative breast cancer (TNBC), defined by quantitative histologic criteria as T-cell desert and T-cell infiltrated (TCI), were compared via label-free quantitative protein mass spectrometry of material extracted directly from targeted regions of formalin-fixed, paraffin-embedded tissue sections. Of 2934 proteins quantitated, 439 were significantly differentially abundant, among which 361 were overabundant in TCI-TNBC. The 361-protein group included proteins involved in major histocompatibility complex-I antigen processing and presentation, viral defense, DNA damage response, and innate immune signaling. Immunohistochemical validation of selected proteins showed good positive correlation between neoplastic cell histoscores and label-free quantitation. Extension of immunohistochemical analysis to a total of 58 inositol polyphosphate 4-phosphatase type II–negative TNBC confirmed elevated levels of the DNA damage sensor interferon-γ–inducible protein 16, inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC), and pore-forming protein gasdermin D in TCI-TNBC neoplastic cells. By contrast, cGMP-AMP synthase inhibitor barrier to autointegration factor (BAF) was elevated in the neoplastic cells of T-cell desert TNBC. These findings demonstrate a previously unknown correlation between the degree of T-cell infiltration in inositol polyphosphate 4-phosphatase type II–negative TNBC and the levels, in cognate neoplastic cells, of proteins that modulate innate immune signaling in response to DNA damage.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2212-2232"},"PeriodicalIF":4.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987244","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":"Growth Differentiation Factor 11 Evokes Lung Injury, Inflammation, and Fibrosis in Mice through the Activin A Receptor Type II-Like Kinase, 53kDa–Smad2/3 Signaling Pathway","authors":"Qian Li,&nbsp;Hanchao Li,&nbsp;Li Zhu,&nbsp;Lijuan Zhang,&nbsp;Xiaoyan Zheng,&nbsp;Zhiming Hao","doi":"10.1016/j.ajpath.2024.07.016","DOIUrl":"10.1016/j.ajpath.2024.07.016","url":null,"abstract":"<div><div>Growth differentiation factor 11 (GDF11) belongs to the transforming growth factor beta superfamily and participates in various pathophysiological processes. Initially, GDF11 was suggested to act as a rejuvenator by improving age-related phenotypes of the heart, brain, and skeletal muscle in aged mice. Recent studies demonstrate that GDF11 also serves as an adverse risk factor for human frailty and diseases. However, the role of GDF11 in pulmonary fibrosis (PF) remains unclear. This study explored the role and signaling mechanisms of GDF11 in PF. GDF11 expression was markedly up-regulated in fibrotic lung tissues of both humans and mice. Intratracheal administration of commercial recombinant GDF11 caused lung injury, inflammation, and fibrogenesis in mice. Furthermore, adenovirus-mediated secretory expression of mature GDF11 was exacerbated, whereas full-length GDF11 or the GDF11 propeptide (GDF11_1-298) alleviated bleomycin-induced PF in mice. In <em>in vitro</em> experiments, GDF11 suppressed the growth of alveolar and bronchial epithelial cells (A549 and BEAS-2B) and human pulmonary microvascular endothelial cells, promoted fibroblast activation, and induced epithelial/endothelial-mesenchymal transition. These effects corresponded to the phosphorylation of Smad2/3, and blocking activin A receptor type II-like kinase, 53kDa (ALK5)-Smad2/3 signaling abolished the <em>in vivo</em> and <em>in vitro</em> effects of GDF11. In conclusion, these findings provide evidence that GDF11 acts as a potent injurious, proinflammatory, and profibrotic factor in the lungs via the ALK5-Smad2/3 pathway.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2036-2058"},"PeriodicalIF":4.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987245","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":"The Impact of Generative Artificial Intelligence on the External Review of Scientific Manuscripts and Editorial Peer Review Processes","authors":"Chhavi Chauhan ,&nbsp;George Currie","doi":"10.1016/j.ajpath.2024.08.002","DOIUrl":"10.1016/j.ajpath.2024.08.002","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1802-1806"},"PeriodicalIF":4.7,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002864/pdfft?md5=f8d7d2b4899b45e7329e87df654fe78f&pid=1-s2.0-S0002944024002864-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915852","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":"Professional Master of Health Science in Laboratory Medicine","authors":"Avrum I. Gotlieb ,&nbsp;Fang-I Lu ,&nbsp;William Tsui ,&nbsp;Heather Shapiro ,&nbsp;Theodore J. Brown ,&nbsp;G. Scot Hamilton ,&nbsp;Danielle C. Bentley ,&nbsp;George M. Yousef ,&nbsp;Juan Putra ,&nbsp;Rachel Zulla ,&nbsp;Rita A. Kandel","doi":"10.1016/j.ajpath.2024.07.013","DOIUrl":"10.1016/j.ajpath.2024.07.013","url":null,"abstract":"<div><div>A 2-year professional master of health science program at the University of Toronto provides a unique integrated educational program to train allied health science personnel to practice as physician extenders and health care professionals in two high-demand clinical laboratory disciplines, Pathologists' Assistant (PA) and Clinical Embryologist (CE). This report describes an integrated graduate program developed and delivered in a research-intensive laboratory medicine department. The core courses in fundamental biomedical science and in general medical laboratory function and operations formed the foundation on which the requisite clinical skills required to practice as a PA or CE were subsequently delivered as comprehensive CE and PA specialty courses and practicums. Students acquired research skills through courses that teach research methods, critical analysis of research articles, and biostatistics for clinical research scientists. A capstone research project provided students the opportunity to design a research project relevant to the CE or PA fields, perform and analyze the findings, and present the project as an oral abstract and a written scientific article. Students learn to face the clinical challenges by focusing on critical analysis of evidence-based professional practice. The PA field received a 5-year accreditation. CE and PA students presented their clinical research at national and international meetings, with some receiving awards, and published scientific articles. All graduates found meaningful employment in their respective fields, and initial employer response has been favorable.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2000-2006"},"PeriodicalIF":4.7,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915851","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":"This Month in AJP","authors":"","doi":"10.1016/j.ajpath.2024.08.001","DOIUrl":"10.1016/j.ajpath.2024.08.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Page 1801"},"PeriodicalIF":4.7,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024002852/pdfft?md5=5f26ec8e599a5e0268ee6e7a0ac77cc0&pid=1-s2.0-S0002944024002852-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141911345","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}