American Journal of Pathology最新文献_第10页

The Amyloid Cascade Hypothesis: A Conclusion in Search of Support. 淀粉样蛋白级联假说：寻找支持的结论

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-10 DOI: 10.1016/j.ajpath.2024.10.014

Rudy J Castellani, Pouya Jamshidi, Germán Plascencia-Villa, George Perry

{"title":"The Amyloid Cascade Hypothesis: A Conclusion in Search of Support.","authors":"Rudy J Castellani, Pouya Jamshidi, Germán Plascencia-Villa, George Perry","doi":"10.1016/j.ajpath.2024.10.014","DOIUrl":"10.1016/j.ajpath.2024.10.014","url":null,"abstract":"<p><p>The amyloid cascade hypothesis as the etiological underpinning of Alzheimer disease (AD) is supported by a large body of literature, the most influential of which are genetic studies of the 1980s and 1990s. Other evidence includes the neuropathology of Down syndrome, apparent toxicity of oligomeric amyloid-β (Aβ), interactions with apolipoprotein E, and the analogy of cardiac amyloidosis. On the other hand, there is considerable phenotypic heterogeneity among the rare familial AD kindreds, which tempers extrapolation to sporadic AD. Oligomer biology is still in the theoretical realm, with no clinical validation. Apolipoprotein E support for the amyloid cascade and other inferences from the literature are somewhat circular in their logic. Analogy with amyloidoses might also consider secondary amyloidosis, driven by systemic inflammation and treated by treating the underlying etiology. Much of the remaining literature supporting the amyloid cascade is dominated by hypothesis-generating studies. Importantly, we now have a developing evidence base from controlled clinical trials that can potentially inform the issue of Aβ as a cause or driver of disease in sporadic AD. Emerging data provide clear evidence of target engagement. Clinical outcome, however, has been either marginally positive or similar to placebo. Assuming these findings hold, it appears that Aβ neither drives nor mitigates the disease process.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611812","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

Genetic, Epigenetic, and Microenvironmental Drivers of Cholangiocarcinoma 胆管癌的遗传、表观遗传和微环境驱动因素

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-10 DOI: 10.1016/j.ajpath.2024.10.013

Vijay Putatunda , Apinya Jusakul , Lewis Roberts , Xin Wei Wang

{"title":"Genetic, Epigenetic, and Microenvironmental Drivers of Cholangiocarcinoma","authors":"Vijay Putatunda , Apinya Jusakul , Lewis Roberts , Xin Wei Wang","doi":"10.1016/j.ajpath.2024.10.013","DOIUrl":"10.1016/j.ajpath.2024.10.013","url":null,"abstract":"<div><div>Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree that carries a poor prognosis. Multiple features at the genetic, epigenetic, and microenvironmental levels have been identified to better characterize CCA carcinogenesis. Genetic alterations, such as mutations in <em>IDH1</em>/<em>2</em>, <em>BAP1</em>, <em>ARID1A</em>, and <em>FGFR2</em>, play significant roles in CCA pathogenesis, with variations across different subtypes, races/ethnicities, and causes. Epigenetic dysregulation, characterized by DNA methylation and histone modifications, further contributes to the complexity of CCA, influencing gene expression and tumor behavior. Furthermore, CCA cells exchange autocrine and paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment, including cancer-associated fibroblasts and tumor-associated macrophages, further contributing to an immunosuppressive niche that supports tumorigenesis. This review explores the multifaceted genetic, epigenetic, and microenvironmental drivers of CCA. Understanding these diverse mechanisms is essential for characterizing the complex pathways of CCA carcinogenesis and developing targeted therapies to improve patient outcomes.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 362-377"},"PeriodicalIF":4.7,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611795","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

The miR-665/SOST Axis Regulates the Phenotypes of Bone Marrow Mesenchymal Stem Cells and Osteoporotic Symptoms in Female Mice miR-665/SOST 轴调控雌性小鼠骨髓间充质干细胞的表型和骨质疏松症状

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-10-24 DOI: 10.1016/j.ajpath.2024.07.022

Xingxing Zeng , Xianyu Yuan , Hongchun Liao , Yongfang Wei , Qinxuan Wu , Xi Zhu , Qingqing Li , Shijie Chen , Minghua Hu

{"title":"The miR-665/SOST Axis Regulates the Phenotypes of Bone Marrow Mesenchymal Stem Cells and Osteoporotic Symptoms in Female Mice","authors":"Xingxing Zeng , Xianyu Yuan , Hongchun Liao , Yongfang Wei , Qinxuan Wu , Xi Zhu , Qingqing Li , Shijie Chen , Minghua Hu","doi":"10.1016/j.ajpath.2024.07.022","DOIUrl":"10.1016/j.ajpath.2024.07.022","url":null,"abstract":"<div><div>Osteoporosis is a common degenerative skeletal disease among older people, especially postmenopausal women. Bone marrow mesenchymal stem cells (BMSCs), the progenitors of osteoblasts, are essential to the pathophysiology of osteoporosis. Herein, targeting miRNAs with differential expression in dysfunctional BMSCs was accomplished by bioinformatics analysis based on public databases. Target mRNAs were predicted and applied for signaling pathway and function enrichment annotations. <em>In vitro</em> and <em>in vivo</em> effects of selected miRNA on BMSC proliferation and osteogenesis were investigated, the putative binding between selected miRNA and predicted target mRNA was verified, and the co-effects of the miRNA/mRNA axis on BMSCs were determined. miRNA 665 (miR-665) was down-regulated in osteoporotic BMSCs compared with normal BMSCs and elevated in BMSCs experiencing osteogenic differentiation. In BMSCs, miR-665 overexpression promoted cell proliferation and osteogenic differentiation. miR-665 targeted the Wnt signaling inhibitor sclerostin (<em>SOST</em>) and inhibited <em>SOST</em> mRNA and protein expression. <em>SOST</em> overexpression inhibited BMSC cell proliferation and osteogenic differentiation. When co-transduced to BMSCs, <em>SOST</em> knockdown significantly reversed the effects of miR-665 on BMSCs. In ovariectomy (OVX)-induced osteoporosis model mice, OVX remarkably decreased bone mass, whereas miR-665 overexpression partially improved OVX-induced bone mass loss. miR-665 was down-regulated in osteoporotic BMSCs and up-regulated in osteogenically differentiated BMSCs. In conclusion, the miR-665/<em>SOST</em> axis modulates BMSC proliferation, osteogenic differentiation, and OVX-induced osteoporosis in mice, possibly through Wnt signaling.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2059-2075"},"PeriodicalIF":4.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492994","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

This Month in AJP 本月 AJP。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-10-12 DOI: 10.1016/j.ajpath.2024.10.002

引用次数: 0

The Impact of Generative Artificial Intelligence on Research Integrity in Scholarly Publishing 生成式人工智能对学术出版中研究诚信的影响。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-10-11 DOI: 10.1016/j.ajpath.2024.10.001

Chhavi Chauhan , George Currie

引用次数: 0

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":"<div><div>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.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 345-361"},"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":"OA","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

{"title":"Hepatic Nuclear Receptors in Cholestasis-to-Cholangiocarcinoma Pathology","authors":"Inyoung Cheon , Minwook Kim , Kang Ho Kim , Sungjin Ko","doi":"10.1016/j.ajpath.2024.07.023","DOIUrl":"10.1016/j.ajpath.2024.07.023","url":null,"abstract":"<div><div>Cholestasis, characterized by impaired bile flow, is associated with an increased risk of cholangiocarcinoma (CCA), a malignancy originating from the biliary epithelium and hepatocytes. Hepatic nuclear receptors (NRs) are pivotal in regulating bile acid and metabolic homeostasis, and their dysregulation is implicated in cholestatic liver diseases and the progression of liver cancer. This review elucidates the role of various hepatic NRs in the pathogenesis of cholestasis-to-CCA progression. It explores their impact on bile acid metabolism as well as their interactions with other signaling pathways implicated in CCA development. Additionally, it introduces available murine models of cholestasis/primary sclerosing cholangitis leading to CCA and discusses the clinical potential of targeting hepatic NRs as a promising approach for the prevention and treatment of cholestatic liver diseases and CCA. Understanding the complex interplay between hepatic NRs and cholestasis-to-CCA pathology holds promise for the development of novel preventive and therapeutic strategies for this devastating disease.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 409-421"},"PeriodicalIF":4.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339398","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

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