American Journal of Pathology最新文献_第7页

Endoplasmic Reticulum Stress Delays Choroid Development in the HCAR1 Knockout Mouse 内质网应激导致 HCAR1 基因敲除小鼠脉络膜发育延迟

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-26 DOI: 10.1016/j.ajpath.2024.09.002

Monir Modaresinejad , Xiaojuan Yang , Mohammad A. Mohammad Nezhady , Tang Zhu , Emmanuel Bajon , Xin Hou , Houda Tahiri , Pierre Hardy , José C. Rivera , Pierre Lachapelle , Sylvain Chemtob

{"title":"Endoplasmic Reticulum Stress Delays Choroid Development in the HCAR1 Knockout Mouse","authors":"Monir Modaresinejad , Xiaojuan Yang , Mohammad A. Mohammad Nezhady , Tang Zhu , Emmanuel Bajon , Xin Hou , Houda Tahiri , Pierre Hardy , José C. Rivera , Pierre Lachapelle , Sylvain Chemtob","doi":"10.1016/j.ajpath.2024.09.002","DOIUrl":"10.1016/j.ajpath.2024.09.002","url":null,"abstract":"<div><div>The subretina, composed of the choroid and the retinal pigment epithelium (RPE), plays a critical role in proper vision. In addition to phagocytosis of photoreceptor debris, the RPE shuttles oxygen and nutrients to the neuroretina. For their own energy production, RPE cells mainly rely on lactate, a major by-product of glycolysis. Lactate, in turn, conveys most of its biological effects via the hydroxycarboxylic acid receptor 1 (HCAR1). Herein, the lactate-specific receptor, HCAR1, was found to be exclusively expressed in the RPE cells within the subretina, and <em>Hcar1</em><sup><em>−/−</em></sup> mice exhibited a substantially thinner choroidal vasculature during development. Notably, the angiogenic properties of lactate on the choroid were impacted by the absence of <em>Hcar1</em>. HCAR1-deficient mice exhibited elevated endoplasmic reticulum stress along with eukaryotic translation initiation factor 2α phosphorylation, a significant decrease in the global protein translation rate, and a lower proliferation rate of choroidal vasculature. Strikingly, inhibition of the integrated stress response using an inhibitor that reverses the effect of eukaryotic translation initiation factor 2α phosphorylation restored protein translation and rescued choroidal thinning. These results provide evidence that lactate signalling via HCAR1 is important for choroidal development/angiogenesis and highlight the importance of this receptor in establishing mature vision.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 12","pages":"Pages 2382-2397"},"PeriodicalIF":4.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339396","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}

引用次数: 0

Morphomolecular Pathology and Genomic Insights into the Cells of Origin of Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma. 胆管癌和肝细胞-胆管癌联合瘤起源细胞的形态分子病理学和基因组学见解。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-26 DOI: 10.1016/j.ajpath.2024.08.014

Rachel V Guest, Benjamin Goeppert, Jean-Charles Nault, Daniela Sia

{"title":"Morphomolecular Pathology and Genomic Insights into the Cells of Origin of Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma.","authors":"Rachel V Guest, Benjamin Goeppert, Jean-Charles Nault, Daniela Sia","doi":"10.1016/j.ajpath.2024.08.014","DOIUrl":"10.1016/j.ajpath.2024.08.014","url":null,"abstract":"<p><p>Cholangiocarcinomas are a highly heterogeneous group of malignancies that, despite recent progress in the understanding of their molecular pathogenesis and clinical management, continue to pose a major challenge to public health. The traditional view posits that cholangiocarcinomas derive from the neoplastic transformation of cholangiocytes lining the biliary tree. However, increasing genetic and experimental evidence has recently pointed to a more complex, and nuanced, scenario for the potential cell of origin of cholangiocarcinomas. Hepatocytes as well as hepatic stem/progenitor cells are being considered as additional potential sources, depending on microenvironmental contexts, including liver injury. The hypothesis of potentially diverse cells of origin for cholangiocarcinoma, albeit controversial, is certainly not surprising given the plasticity of the cells populating the liver as well as the existence of liver cancer subtypes with mixed histologic and molecular features. This review carefully examines the current pathologic, genomic, and experimental evidence supporting the existence of multiple cells of origin of liver and biliary tract cancers, with particular focus on cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endothelial c-Src Mediates Neovascular Tuft Formation in Oxygen-Induced Retinopathy 内皮细胞 c-Src 在氧诱导视网膜病变中介导新生血管丛的形成

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-25 DOI: 10.1016/j.ajpath.2024.09.003

Emmanuelle Frampton, Priyanka Som, Brittany Hill, Alexander Yu, Marina Naval-Sanchez, Chistian M. Nefzger, Ivar Noordstra, Emma Gordon, Lilian Schimmel

{"title":"Endothelial c-Src Mediates Neovascular Tuft Formation in Oxygen-Induced Retinopathy","authors":"Emmanuelle Frampton, Priyanka Som, Brittany Hill, Alexander Yu, Marina Naval-Sanchez, Chistian M. Nefzger, Ivar Noordstra, Emma Gordon, Lilian Schimmel","doi":"10.1016/j.ajpath.2024.09.003","DOIUrl":"10.1016/j.ajpath.2024.09.003","url":null,"abstract":"<div><div>Vascular retinopathy, characterized by abnormal blood vessel growth in the retina, frequently results in vision impairment or loss. Neovascular tufts, a distinctive pathologic feature of this condition, are highly leaky blood vessel structures, exacerbating secondary complications. Despite their clinical significance, the mechanisms underlying tuft development are not fully elucidated, posing challenges for effective management and treatment of vascular retinopathy. This study investigates the role of cellular (c)-Src in neovascular tuft formation. Although c-Src is a pivotal regulator in developmental angiogenesis within the retinal vasculature, its specific role in governing pathologic retinal angiogenesis remains to be fully understood. Herein, the oxygen-induced retinopathy model was used for neovascular tuft formation in both Cre-mediated vascular-specific c-Src knockout mice and wild-type littermates. High-resolution imaging and analysis of isolated retinas were conducted. c-Src depletion demonstrated a significant reduction in neovascular tufts within the oxygen-induced retinopathy model. This decrease in tuft formation was observed independently of any alterations in cell death, cell proliferation, or cell adhesion, and the absence of c-Src did not impact tuft pericyte coverage and junctional morphology. These findings underline the critical role of c-Src in the pathogenesis of neovascular tufts in vascular retinopathy. Understanding the molecular mechanisms involving c-Src may offer valuable insights for the development of targeted therapies aimed at mitigating vision-threatening complications associated with retinopathy.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 12","pages":"Pages 2239-2251"},"PeriodicalIF":4.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339397","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}

引用次数: 0

Hepatic Nuclear Receptors in Cholestasis-to-Cholangiocarcinoma Pathology. 胆汁淤积到胆管癌病理学中的肝核受体

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-24 DOI: 10.1016/j.ajpath.2024.07.023

Inyoung Cheon, Minwook Kim, Kang Ho Kim, Sungjin Ko

引用次数: 0

Calpain-1 Up-Regulation Promotes Bleomycin-Induced Pulmonary Fibrosis by Activating Ferroptosis 钙蛋白酶-1的上调通过激活铁蛋白沉积促进博莱霉素诱导的肺纤维化。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-24 DOI: 10.1016/j.ajpath.2024.09.004

Silin Wei, Yu Liu, Chenyang Ran, Yunhan Li, Bailin Tang, Meili Lu, Hongxin Wang

{"title":"Calpain-1 Up-Regulation Promotes Bleomycin-Induced Pulmonary Fibrosis by Activating Ferroptosis","authors":"Silin Wei, Yu Liu, Chenyang Ran, Yunhan Li, Bailin Tang, Meili Lu, Hongxin Wang","doi":"10.1016/j.ajpath.2024.09.004","DOIUrl":"10.1016/j.ajpath.2024.09.004","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease. Calpain-1 is an effective therapeutic target for vascular endothelial dysfunction and pulmonary hypertension. However, the role of calpain-1 in bleomycin (BLM)–induced IPF has not been defined. The aim of this study was to assess the targeting of calpain-1 by activating ferroptosis in BLM-treated knockout mice and murine lung epithelial-12 cells. The role of calpain-1 in the regulation of IPF was investigated using a BLM-induced IPF mouse model. The results of this study showed that increased expression of calpain-1 was accompanied by increased fibrosis, lipid peroxidation, iron ion accumulation, and Yes-associated protein (YAP) levels and decreased levels of phosphorylated adenosine 5′-monophosphate–activated protein kinase (p-AMPK) in BLM-induced IPF. MDL-28170 (calpain-1 inhibition) treatment and calpain-1 knockdown alleviated ferroptosis and IPF induced by BLM. Overexpression of calpain-1 in murine lung epithelial-12 cells further exacerbated iron accumulation and IPF. Mechanistically, lentivirus-mediated up-regulation of calpain-1 inhibited AMPK activity and promoted the nuclear translocation of YAP, leading to high levels of acyl-CoA synthetase long-chain family 4 and transferrin receptor protein 1 and triggering a ferroptosis response that ultimately exacerbated BLM-induced lung fibrosis. Calpain-1 inhibition reversed these results and ameliorated BLM-induced IPF. In conclusion, these findings suggest that the calpain-1–acyl-CoA synthetase long-chain family 4–transferrin receptor protein 1–ferroptosis–positive regulatory axis contributes to BLM-induced IPF, which indicates that calpain-1 has potential therapeutic value for the treatment of IPF.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 12","pages":"Pages 2272-2289"},"PeriodicalIF":4.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339395","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}

引用次数: 0

Retraction notice to “Bone Marrow Ablation Demonstrates That Excess Endogenous Parathyroid Hormone Plays Distinct Roles in Trabecular and Cortical Bone” [Am J Pathol 181 (2012) 234–244] 骨髓消融显示过量内源性甲状旁腺激素在骨小梁和骨皮质中发挥着不同作用》的撤稿通知 [Am J Pathol 181 (2012) 234-244]

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-23 DOI: 10.1016/j.ajpath.2024.08.004

Jun Yan , Weiwei Sun , Jing Zhang , David Goltzman , Dengshun Miao

引用次数: 0

Glucocorticoid Receptor Signaling Is Critical for Mouse Corneal Development, Inhibition of Inflammatory Response, and Neovascularization of the Cornea 糖皮质激素受体信号对小鼠角膜发育、炎症反应抑制和角膜新生血管至关重要

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-23 DOI: 10.1016/j.ajpath.2024.06.005

Mahita Kadmiel , David Diaz-Jimenez , Robert H. Oakley , Maria G. Petrillo , Bo He , Xiaojiang Xu , John A. Cidlowski

{"title":"Glucocorticoid Receptor Signaling Is Critical for Mouse Corneal Development, Inhibition of Inflammatory Response, and Neovascularization of the Cornea","authors":"Mahita Kadmiel , David Diaz-Jimenez , Robert H. Oakley , Maria G. Petrillo , Bo He , Xiaojiang Xu , John A. Cidlowski","doi":"10.1016/j.ajpath.2024.06.005","DOIUrl":"10.1016/j.ajpath.2024.06.005","url":null,"abstract":"<div><div>The cornea protects the interior of the eye from external agents such as bacteria, viruses, and debris. Synthetic glucocorticoids are widely prescribed in the treatment of ocular infections and disorders. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR); however, the molecular and physiological functions of GR signaling in the cornea are poorly understood. This study found that treatment of mice with glucocorticoid eye drops led to a profound regulation of the corneal transcriptome. These glucocorticoid-regulated genes were associated with multiple biological functions, including the immune response. To understand the direct role of GR signaling in the cornea, mice with conditional knockout of GRs in the corneal epithelium were generated. Mice lacking corneal GRs exhibited microphthalmia, loss of pupils, a deformed and opaque lens, and mislocalization of key structural proteins within the corneal epithelial layers. Global transcriptomic approaches revealed that loss of GR signaling in the cornea also resulted in the dysregulation of a large cohort of genes strongly associated with an enhanced inflammatory response. Finally, corneal GR signaling was required for preventing neovascularization of blood and lymphatic vessels and thereby immune cell infiltration of the cornea. These results reveal that corneal GR signaling plays a critical role in ocular development and in maintaining the homeostasis of the eye.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 10","pages":"Pages 1938-1950"},"PeriodicalIF":4.7,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142311819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Testosterone-Induced H3K27 Deacetylation Participates in Granulosa Cell Proliferation Suppression and Pathogenesis of Polycystic Ovary Syndrome 睾酮诱导的 H3K27 去乙酰化参与了颗粒细胞增殖抑制和多囊卵巢综合征的发病机制。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-05 DOI: 10.1016/j.ajpath.2024.08.012

Xiaomei Tong , Zhanhong Hu , Hanjing Zhou , Yingyi Zhang , Yin-Li Zhang , Songying Zhang , Jiamin Jin

{"title":"Testosterone-Induced H3K27 Deacetylation Participates in Granulosa Cell Proliferation Suppression and Pathogenesis of Polycystic Ovary Syndrome","authors":"Xiaomei Tong , Zhanhong Hu , Hanjing Zhou , Yingyi Zhang , Yin-Li Zhang , Songying Zhang , Jiamin Jin","doi":"10.1016/j.ajpath.2024.08.012","DOIUrl":"10.1016/j.ajpath.2024.08.012","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) is the leading cause of infertility in reproductive-age women. Hyperandrogenism, polycystic ovaries, and chronic anovulation are its typical clinical features. However, the correlation between hyperandrogenism and ovarian follicle growth aberrations remains poorly understood. To advance our understanding of the molecular alterations in ovarian granulosa cells (GCs) with excessive androgen, epigenetic changes and affected gene expression in human granulosa-lutein cells and immortalized human GCs were evaluated. A PCOS mouse model induced by dihydrotestosterone was also established. This study found that excessive testosterone significantly decreased the acetylation of lysine 27 on histone H3 (H3K27Ac). H3K27Ac chromatin immunoprecipitation–sequencing data showed down-regulated expression of cell cycle–related genes <em>CCND1</em>, <em>CCND3</em>, and <em>PCNA</em>, which was confirmed by real-time quantitative PCR and Western blot analysis. Testosterone application impeding cell proliferation was also shown by Ki-67 immunofluorescence and flow-cytometric analysis. Moreover, testosterone influenced casein kinase 2 alpha (CK2α) nuclear translocation, which increased the phosphorylation level of histone deacetylase 2 (HDAC2). Inhibition of CK2α nuclear translocation or silenced <em>HDAC2</em> expression efficiently retarded H3K27 acetylation. PCOS mouse model experiments also demonstrated decreased H3K27Ac and enhanced HDAC2 phosphorylation in GCs. Cell proliferation–related genes were also down-regulated in PCOS mouse GCs. In conclusion, hyperandrogenism in human and mouse GCs caused H3K27Ac aberrations, which are associated with CK2α nuclear translocation and HDAC2 phosphorylation, participating in abnormal follicle development in patients with PCOS.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 12","pages":"Pages 2326-2340"},"PeriodicalIF":4.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144954","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}

引用次数: 0

This Month in AJP 本月 AJP。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-05 DOI: 10.1016/j.ajpath.2024.09.001

引用次数: 0

Histopathologic Differential Diagnosis and Estrogen Receptor/Progesterone Receptor Immunohistochemical Evaluation of Breast Carcinoma Using a Deep Learning–Based Artificial Intelligence Architecture 使用基于深度学习的人工智能架构对乳腺癌进行组织病理学鉴别诊断和雌激素受体/孕激素受体免疫组化评估。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-09-04 DOI: 10.1016/j.ajpath.2024.08.011

Zhi Han , Shihong Ding , Baichen Liu , Yandong Tang , Xueshan Qiu , Enhua Wang , Huanyu Zhao

{"title":"Histopathologic Differential Diagnosis and Estrogen Receptor/Progesterone Receptor Immunohistochemical Evaluation of Breast Carcinoma Using a Deep Learning–Based Artificial Intelligence Architecture","authors":"Zhi Han , Shihong Ding , Baichen Liu , Yandong Tang , Xueshan Qiu , Enhua Wang , Huanyu Zhao","doi":"10.1016/j.ajpath.2024.08.011","DOIUrl":"10.1016/j.ajpath.2024.08.011","url":null,"abstract":"<div><div>In breast carcinoma, invasive ductal carcinoma (IDC) is the most common histopathologic subtype, and ductal carcinoma <em>in situ</em> (DCIS) is a precursor of IDC. These two often occur concomitantly. The immunohistochemical staining of estrogen receptor (ER)/progesterone receptor (PR) in IDC/DCIS on histopathologic whole slide images (WSIs) can predict the prognosis of patients. Artificial intelligence (AI) technology has the potential to substantially reduce the interobserver variability among pathologists reading WSIs. Herein, IDC/DCIS detection was conducted by a deep learning approach, including faster region-based convolutional neural network (Faster R-CNN), RetinaNet, single-shot multibox detector 300 (SSD300), you only look once (YOLO) v3, YOLOv5, YOLOv7, YOLOv8, and Swin transformer. Their performance was estimated by mean average precision (mAP) values. Cell recognition and counting were performed using AI technology to evaluate the intensity and proportion of ER/PR-immunostained cancer cells in IDC/DCIS. A three-round ring study (RS) was conducted to assess WSIs. A database for modelling the underlying probability distribution of a data set with labels was established. YOLOv8 exhibited the highest detection performance with an mAP at 0.5 of 0.944 and an mAP at 0.5 to 0.95 of 0.790. With the assistance of YOLOv8, the scoring concordance across all pathologists was boosted to excellent in RS3 (0.970) from moderate in RS1 (0.724) and good in RS2 (0.812). Deep learning detection can be applied in the clinicopathologic field. Herein, a novel AI architecture and well-organized data set were developed to facilitate the histopathologic diagnosis of IDC/DCIS and immunostaining scoring of ER/PR.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 12","pages":"Pages 2313-2325"},"PeriodicalIF":4.7,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0