American Journal of Pathology最新文献_第5页

The American Journal of Pathology’s Contribution to Advancing the Understanding of the Pathogenesis of Atherosclerosis 《美国病理学杂志》对推进对动脉粥样硬化发病机制理解的贡献

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-23 DOI: 10.1016/j.ajpath.2024.11.012

Avrum I. Gotlieb

引用次数: 0

Crosstalk between Hepatic Stellate Cells and Hepatic Macrophages in Metabolic Dysfunction–Associated Steatohepatitis 代谢功能障碍相关脂肪性肝炎中肝星状细胞和肝巨噬细胞间的串扰

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-23 DOI: 10.1016/j.ajpath.2025.02.003

Haoran Zhong , Chen Liu , Zhiwei Huang , Peng Tan , Hao Chen , Wenguang Fu

引用次数: 0

This Month in AJP 本月在AJP。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-15 DOI: 10.1016/j.ajpath.2025.05.001

引用次数: 0

Alcohol-Associated Hepatocarcinogenesis: Wnt/β-Catenin in Action. 酒精相关肝癌的发生：Wnt/β-连环蛋白的作用

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-09 DOI: 10.1016/j.ajpath.2025.04.016

Yuhua Xue, Tian Tian, Melak Ottallah, Mahfuza Mannan, Joshua Barkin, Brady Jin-Smith, Liya Pi

{"title":"Alcohol-Associated Hepatocarcinogenesis: Wnt/β-Catenin in Action.","authors":"Yuhua Xue, Tian Tian, Melak Ottallah, Mahfuza Mannan, Joshua Barkin, Brady Jin-Smith, Liya Pi","doi":"10.1016/j.ajpath.2025.04.016","DOIUrl":"10.1016/j.ajpath.2025.04.016","url":null,"abstract":"<p><p>Long-term alcohol consumption is a leading global health concern, primarily due to its deleterious effects on liver function and its well-established association with hepatocellular carcinoma. Alcohol-related liver disease (ALD) encompasses a continuum-from reversible hepatic steatosis and steatohepatitis through progressive fibrosis and cirrhosis to overt hepatocellular carcinoma. Accumulating studies have revealed that the Wnt/β-catenin signaling pathway is an essential regulator in ALD pathogenesis, orchestrating diverse molecular, immunologic, and epigenetic processes. Aberrant β-catenin activity disrupts redox homeostasis, promotes chronic inflammation, drives extracellular matrix remodeling, and alters hepatocyte cell fate, thereby creating a microenvironment that is highly conducive to carcinogenesis. This article provides a systematic review of the significant function of Wnt/β-catenin signaling in ALD, emphasizing its regulatory impact on liver fat accumulation, its inflammatory role in steatohepatitis, its involvement in fibrogenesis, and its tumor-promoting effects in alcohol-related hepatocellular carcinoma. In addition, emerging therapeutic strategies that offer potential for early identification and tailored therapy of ALD are explored-including direct Wnt modulators, combinatory therapeutics, and precision medicine approaches.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957752","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

Cholestasis in Alcohol-Associated Liver Disease. 酒精相关性肝病中的胆汁淤积

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-09 DOI: 10.1016/j.ajpath.2025.04.015

Shengmin Yan, Xiao-Ming Yin

引用次数: 0

Computationally Enabled Polychromatic Polarized Imaging Enables Mapping of Matrix Architectures that Promote Pancreatic Ductal Adenocarcinoma Dissemination 计算支持的多色偏振成像可以绘制促进胰腺导管腺癌扩散的基质结构。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-09 DOI: 10.1016/j.ajpath.2025.04.017

Guhan Qian , Hongrong Zhang , Yuming Liu , Michael Shribak , Kevin W. Eliceiri , Paolo P. Provenzano

{"title":"Computationally Enabled Polychromatic Polarized Imaging Enables Mapping of Matrix Architectures that Promote Pancreatic Ductal Adenocarcinoma Dissemination","authors":"Guhan Qian , Hongrong Zhang , Yuming Liu , Michael Shribak , Kevin W. Eliceiri , Paolo P. Provenzano","doi":"10.1016/j.ajpath.2025.04.017","DOIUrl":"10.1016/j.ajpath.2025.04.017","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDA) is a highly metastatic and lethal disease. In PDA, extracellular matrix (ECM) architectures, known as tumor-associated collagen signatures (TACSs), regulate invasion and metastatic spread in both early dissemination and late-stage disease. As such, TACS has been suggested as a biomarker to aid in pathologic assessment. However, despite its significance, approaches to quantitatively capture these ECM patterns currently require advanced optical systems with signaling processing analysis. Herein, an expansion of polychromatic polarized microscopy (PPM) with inherent angular information coupled with machine learning and computational pixel-wise analysis of TACS was used to accurately capture TACS architectures in hematoxylin and eosin–stained histology sections directly through PPM contrast. Moreover, PPM facilitated identification of transitions to dissemination architectures (ie, transitions from sequestration through expansion to dissemination from both pancreatic intraepithelial neoplasias and throughout PDA). Lastly, PPM evaluation of architectures in liver metastases, the most common metastatic site for PDA, demonstrated TACS-mediated focal and local invasion as well as identification of unique patterns anchoring aligned fibers into normal-adjacent tumor, suggesting that these patterns may be precursors to metastasis expansion and local spread from micrometastatic lesions. Combined, these findings demonstrate that PPM coupled to computational platforms is a powerful tool for analyzing ECM architecture that can be used to advance cancer microenvironment studies and provide clinically relevant diagnostic information.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Pages 1242-1253"},"PeriodicalIF":4.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966629","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

The Patatin-Like Phospholipase Domain-Containing 3 148M Variant Exacerbates Alcohol-Induced Liver Injury and Tumorigenesis in Mice. PNPLA3 148M变异加重了小鼠酒精诱导的肝损伤和肿瘤发生。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-09 DOI: 10.1016/j.ajpath.2025.04.014

Jung-Hyo Cho, Hyeong-Geug Kim, Menghao Huang, Shen Wang, Sheng Liu, Alex Lu, Kyle McCrocklin, Yang Zhang, Zhigang Fang, Juexin Wang, Wanqing Liu, Jun Wan, X Charlie Dong

{"title":"The Patatin-Like Phospholipase Domain-Containing 3 148M Variant Exacerbates Alcohol-Induced Liver Injury and Tumorigenesis in Mice.","authors":"Jung-Hyo Cho, Hyeong-Geug Kim, Menghao Huang, Shen Wang, Sheng Liu, Alex Lu, Kyle McCrocklin, Yang Zhang, Zhigang Fang, Juexin Wang, Wanqing Liu, Jun Wan, X Charlie Dong","doi":"10.1016/j.ajpath.2025.04.014","DOIUrl":"10.1016/j.ajpath.2025.04.014","url":null,"abstract":"<p><p>Patatin-like phospholipase domain-containing 3 (PNPLA3) protein 148M variant is strongly associated with cirrhosis and hepatocellular carcinoma (HCC); however, the underlying mechanisms remain elusive. This study aimed to elucidate the role of the PNPLA3<sup>148M</sup> variant in alcohol-related HCC development. Control and humanized PNPLA3<sup>148M</sup> transgenic mice were fed with an ethanol-containing diet for 12 weeks. The animals were examined for liver tumors. After the alcohol feeding, the PNPLA3<sup>148M</sup> mice had twofold higher liver cancer incidence rates and larger tumor sizes than those in the control mice. Cancer stem cell markers in the PNPLA3<sup>148M</sup> mouse livers were elevated relative to those in the control mouse livers. Alcohol detoxification was impaired in the PNPLA3<sup>148M</sup> mouse livers. Hepatic oxidative stress and DNA damage were elevated in the PNPLA3<sup>148M</sup> mice. Wnt/β-catenin and Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (TAZ) were activated in the PNPLA3<sup>148M</sup> mouse livers. The data suggest that the PNPLA3<sup>148M</sup> variant has a strong interaction with alcohol in HCC development through attenuation of alcohol detoxification and promotion of oncogenic pathways. Targeting the PNPLA3<sup>148M</sup> variant might be useful for the prevention or treatment of alcohol-associated HCC in patients carrying this variant.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959681","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

Deciphering the Dialogue between Brain Tumors, Neurons, and Astrocytes 破解脑肿瘤、神经元和星形胶质细胞之间的对话。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-07 DOI: 10.1016/j.ajpath.2025.04.013

Leevi H. Westerlund , Camilla K. Bergström , Pirjo M. Laakkonen , Vadim Le Joncour

{"title":"Deciphering the Dialogue between Brain Tumors, Neurons, and Astrocytes","authors":"Leevi H. Westerlund , Camilla K. Bergström , Pirjo M. Laakkonen , Vadim Le Joncour","doi":"10.1016/j.ajpath.2025.04.013","DOIUrl":"10.1016/j.ajpath.2025.04.013","url":null,"abstract":"<div><div>Glioblastoma and brain metastases from peripheral tumors account for most cases of tumors in the central nervous system while also being the deadliest. From a structural point of view, malignant brain tumors are classically characterized by hypercellularity of glioma and vascular endothelial cells. Given these atypical histologic features, glioblastoma and brain metastases have long been considered as “foreign” entities with few to no connections to the brain parenchyma. The identification of intricate connections established between glioblastoma cells and the brain parenchyma paired with the ability of peripheral metastatic cells to form functional synapses with neurons challenged the concept of brain tumors disconnected from the central nervous system. Tumor cell integration to the brain parenchyma alters brain functionality in patients and accelerates cancer progression. Next-generation precision medicine should therefore attempt to disconnect brain cancer cells from the brain. This review encompasses recent discoveries in the mechanisms underlying these relationships and discusses the impact of these connections on tumor progression. It also summarizes the therapeutic opportunities of interrupting the dialogue between healthy and neoplastic brains.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Pages 1193-1208"},"PeriodicalIF":4.7,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964178","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

Uncovering the Unique Roles of Cathepsins B and L in Purkinje Cells Using Nervous System-Specific CTSB and CTSL Double-Deficient Mice. 利用神经系统特异性CTSB和CTSL双缺陷小鼠揭示组织蛋白酶B和L在浦肯野细胞中的独特作用

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-05-02 DOI: 10.1016/j.ajpath.2025.04.011

Takahito Sanada, Chigure Suzuki, Junji Yamaguchi, Takashi Ueno, Juan Alejandro Oliva Trejo, Soichiro Kakuta, Norihiro Tada, Masaki Ohmuraya, Isei Tanida, Yasuo Uchiyama

{"title":"Uncovering the Unique Roles of Cathepsins B and L in Purkinje Cells Using Nervous System-Specific CTSB and CTSL Double-Deficient Mice.","authors":"Takahito Sanada, Chigure Suzuki, Junji Yamaguchi, Takashi Ueno, Juan Alejandro Oliva Trejo, Soichiro Kakuta, Norihiro Tada, Masaki Ohmuraya, Isei Tanida, Yasuo Uchiyama","doi":"10.1016/j.ajpath.2025.04.011","DOIUrl":"10.1016/j.ajpath.2025.04.011","url":null,"abstract":"<p><p>Defects in the autophagy-lysosomal degradation pathway contribute to neurodegenerative diseases. Cathepsins B (CtsB) and L (CtsL) are major lysosomal cysteine proteases. Mice deficient in both CtsB and CtsL exhibit abnormalities not only in neural tissue but in other organs, such as heart and liver, with most dying at approximately 16 days of age. To investigate the roles of CtsB and CtsL in the nervous system, nervous system-specific CTSB and CTSL double-knockout mice (CtsB/L-NES) were generated. These mice displayed tail elevation, motor dysfunction, and hyperactivity. In adulthood, they developed cerebellar atrophy, with Purkinje cells in the cerebellar cortex showing selective loss of phospholipase C β4-positive and Zebrin II-negative Purkinje cells in a striped pattern. Ubiquitin-positive structures accumulated in the perikarya and axons of Purkinje cells, reflecting impaired autophagy-lysosomal degradation. Activation of astrocytes and microglia was observed in Purkinje cell loss regions. Electron microscopy revealed granular osmiophilic deposit-like structures in perikarya, autophagosome-like accumulations in axons, and a reduction in synaptic vesicles at active regions of swollen axon terminals in Purkinje cells. Additionally, neuronal loss was observed specifically in the ventral posterior lateral and ventral posterior medial nuclei of the thalamus. These findings demonstrate CtsB and CtsL are essential for survival of Purkinje cells in the cerebellum and neurons in the ventral posterior lateral and ventral posterior medial nuclei of the thalamus.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961951","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

FKBP10 Silencing Alleviates Gluteal Muscle Contracture by Inhibiting Fibrosis and Restoring Autophagy via HSP47/SMAD3 Pathway Inactivation FKBP10沉默通过HSP47/SMAD3通路失活抑制纤维化和恢复自噬减轻臀肌挛缩

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-04-30 DOI: 10.1016/j.ajpath.2025.04.005

Haixia Xu , Jingjiang Yao , Qiao Jin , Ji Yao , Lu Ren , Jiaoyan Zhu , Wei Luo , Peng Zheng , Liangjun Li , Junjie Zhou

{"title":"FKBP10 Silencing Alleviates Gluteal Muscle Contracture by Inhibiting Fibrosis and Restoring Autophagy via HSP47/SMAD3 Pathway Inactivation","authors":"Haixia Xu , Jingjiang Yao , Qiao Jin , Ji Yao , Lu Ren , Jiaoyan Zhu , Wei Luo , Peng Zheng , Liangjun Li , Junjie Zhou","doi":"10.1016/j.ajpath.2025.04.005","DOIUrl":"10.1016/j.ajpath.2025.04.005","url":null,"abstract":"<div><div>FKBP prolyl isomerase 10 (FKBP10) plays a key role in fibrosis-driven progression of gluteal muscle contracture (GMC). This study investigated the molecular mechanism of FKBP10 in GMC progression. Expression levels of FKBP10, heat shock protein 47 (HSP47), SMAD3, autophagy, and fibrosis-related indicators were analyzed for correlations. The GMC rat model was constructed by injecting methanol penicillin. The interaction between FKBP10 and HSP47 was also assessed. FKBP10 expression was up-regulated in the gluteal muscle of patients with GMC and rats, accompanied by obvious damage and fibrosis. Elevated levels of transforming growth factor beta 1 (TGF-β1), α-smooth muscle actin (α-SMA), collagen I, collagen III, vimentin, fibronectin, p62, and LC3, along with decreased levels of matrix metalloproteinase-9 and LC3II/I, Beclin 1, p62, and ATG7, indicated weakened autophagy. FKBP10 expression correlated negatively with autophagy indicators and positively with HSP47 and fibrosis indicators. FKBP10 interacted with HSP47. Knockdown of FKBP10 down-regulated the levels of HSP47 and phosphorylated SMAD3/SMAD3. Furthermore, knockdown of FKBP10, HSP47, and rapamycin partially reversed the TGF-β1–induced effect. Conversely, 3-methyl adenine and HSP47 overexpression enhanced TGF-β1–induced effects. In GMC rats, FKBP10 knockdown reduced tissue damage and fibrosis, reversed HSP47, phosphorylated SMAD3/SMAD3, fibrosis, and autophagy indicator levels, and reduced autophagy and LC3 levels. In summary, silencing FKBP10 inactivated the HSP47/SMAD3 signaling pathway, inhibited fibrosis, and ameliorated autophagy defects, thereby alleviating GMC.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 8","pages":"Pages 1504-1522"},"PeriodicalIF":4.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962063","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