American Journal of Pathology最新文献_第3页

TIMP-2 Promotes Wound Healing by Suppressing Matrix Metalloproteinases and Inflammatory Cytokines in Corneal Epithelial Cells.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-26 DOI: 10.1016/j.ajpath.2024.11.007

Olufemi S Folorunso, Nishant R Sinha, Aastha Singh, Lei Xi, Vinay K Pulimamidi, WonKyung J Cho, Sharad K Mittal, Sunil K Chauhan

{"title":"TIMP-2 Promotes Wound Healing by Suppressing Matrix Metalloproteinases and Inflammatory Cytokines in Corneal Epithelial Cells.","authors":"Olufemi S Folorunso, Nishant R Sinha, Aastha Singh, Lei Xi, Vinay K Pulimamidi, WonKyung J Cho, Sharad K Mittal, Sunil K Chauhan","doi":"10.1016/j.ajpath.2024.11.007","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.11.007","url":null,"abstract":"Tissue inhibitors of metalloproteinases (TIMPs) modulate extracellular matrix (ECM) remodeling for maintaining homeostasis and promoting cell migration and proliferation. Pathological conditions can alter TIMP homeostasis and aggravate disease progression. The roles of TIMPs have been studied in tissue-related disorders; however, their contributions to tissue repair during corneal injury are undefined. Here, the TIMP expression in human corneal epithelial (HCLE) cells under homeostatic and inflammatory milieus was profiled to examine their contribution to the healing of injured cornea epithelia. Transcriptionally, TIMP-2 was highly expressed in HCLE when stimulated with 100 ng/mL IL-1β or scratch-wounded. Unlike TIMP-1, recombinant TIMP-2 (rTIMP-2) significantly promoted epithelial cell wound closure compared to untreated and TIMP-2-neutralizing conditions. At 12 hours, the Ki-67+ cells significantly increased 3-fold compared to untreated cells, suggesting that rTIMP-2 is associated with cell proliferation. Furthermore, rTIMP-2 treatment significantly suppressed inflammatory cytokine expression (IL-1β, IL-6, IL-8, and TNFα) and injury-induced matrix metalloproteinases (MMP-1, -2, -3, -9, -10, and -13). Topical treatment of injured mouse cornea with 0.1 mg/mL rTIMP-2 significantly promoted corneal re-epithelialization and improved tissue integrity. The treatment suppressed the expression of inflammatory cytokines and MMPs, as well as the infiltration of neutrophils at the injury site. These findings indicate that TIMP-2 promotes faster wound healing by suppressing injury-induced inflammation and MMP expression, suggesting a potential therapeutic target for corneal wound management.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891639","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

TMCO1-Deficient Mice Exhibit a High Incidence of Otitis Media Associated with Impaired Bone Homeostasis in the Middle Ear.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-25 DOI: 10.1016/j.ajpath.2024.11.008

Yaning Dong, Peng Ma, Shuli Wang, Lan Wang, Yingying Chen, Fangfang Zhao, Keyan Yang, Xiaolin Zhang, Hongchun Zhao, Bo Li, Ruishuang Geng, Tie-Shan Tang, Qingyin Zheng, Tihua Zheng

{"title":"TMCO1-Deficient Mice Exhibit a High Incidence of Otitis Media Associated with Impaired Bone Homeostasis in the Middle Ear.","authors":"Yaning Dong, Peng Ma, Shuli Wang, Lan Wang, Yingying Chen, Fangfang Zhao, Keyan Yang, Xiaolin Zhang, Hongchun Zhao, Bo Li, Ruishuang Geng, Tie-Shan Tang, Qingyin Zheng, Tihua Zheng","doi":"10.1016/j.ajpath.2024.11.008","DOIUrl":"10.1016/j.ajpath.2024.11.008","url":null,"abstract":"Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome (CFSMR1; Online Inheritance in Man number 213980) is characterized by craniofacial dysmorphism, skeletal anomalies, and mental retardation. However, reports of hearing issues have been limited. To investigate hearing-related aspects of CFSMR1, Tmco1 knockout mice (Tmco1-/-) exhibiting similar symptoms to human patients were used in this study. Otitis media (OM) was discovered in approximately 80% of Tmco1-/- mice, which led to moderate conductive hearing loss at 3 months old and further progressed to deafness 2 months later. Pathology studies of Tmco1-/- mice revealed a thickened middle ear (ME) epithelium and pronounced inflammatory infiltrates in the ME cavity and Eustachian tube of Tmco1-/- OM mice. Micro-computed tomography scan of 5-month-old Tmco1-/- OM mice showed significantly reduced ME volume and ME malformation. Tartrate-resistant acid phosphatase and Runt-related transcription factor 2, receptor activator of NF-κB ligand expression in ME revealed increased osteoclast activity and significantly decreased bone formation, suggesting potential causes of ME malformation. This study represents the first report of the audiological characteristics and the elucidation of potential mechanisms in Tmco1-/- mice. It enriches our understanding of the phenotypes associated with CFSMR1 in the field of otology and provides a promising model for chronic OM with conductive hearing loss.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891640","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

Characterization and Role of Glucagon-Like Peptide 1 Receptor in the Lacrimal Gland: Novel Insights into Diabetic Dry Eye Pathogenesis.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-25 DOI: 10.1016/j.ajpath.2024.12.003

Yan Sun, Yue Zhang, Fan Shi, Ye Li, Congyao Wang, Fenfen Yu, Tingting Chen, Xia Dong, Yuqi Xu, Yu Zhao, Pengxia Wan

{"title":"Characterization and Role of Glucagon-Like Peptide 1 Receptor in the Lacrimal Gland: Novel Insights into Diabetic Dry Eye Pathogenesis.","authors":"Yan Sun, Yue Zhang, Fan Shi, Ye Li, Congyao Wang, Fenfen Yu, Tingting Chen, Xia Dong, Yuqi Xu, Yu Zhao, Pengxia Wan","doi":"10.1016/j.ajpath.2024.12.003","DOIUrl":"10.1016/j.ajpath.2024.12.003","url":null,"abstract":"This study aimed to investigate the expression of glucagon-like peptide 1 receptor (GLP-1R) in the lacrimal gland and explore the effects of topical application of GLP-1R agonist on lacrimal gland function in a murine model of type 1 diabetes. Tear secretion was evaluated using phenol red threads, RNA sequencing was used to explore gene expression profiles associated with hyperglycemia-induced lacrimal gland injuries, and histologic analysis was conducted to evaluate the degree of damage. The expression of GLP-1R in the lacrimal gland was first identified, and a down-regulation trend associated with diabetes was observed. RNA-sequencing data from lacrimal gland tissues revealed that differentially expressed genes were enriched in inflammatory response pathways. Histologic analysis demonstrated persistent hyperglycemia-induced infiltration of inflammatory cells and progressive fibrosis in the lacrimal gland, resulting in atrophy and diminished tear secretion. Topical application of liraglutide effectively attenuated inflammation and alleviated fibrosis, thus promoting tear production in diabetic mice. Additionally, local intervention with liraglutide could promote autophagy degradation function in the lacrimal gland. This study represents the first validation of GLP-1R expression in the lacrimal gland and its down-regulation induced by diabetes; furthermore, these findings demonstrate that topical administration of liraglutide eye drops, a GLP-1R agonist, can effectively mitigate hyperglycemia-induced damage in the lacrimal gland while enhancing tear secretion.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891600","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

IL-35 May Prevent the Exacerbation of Aspiration Pneumonia Involving Porphyromonas gingivalis by Suppressing IL-17 Production.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-24 DOI: 10.1016/j.ajpath.2024.11.009

Shotaro Kawamura, Hisashi Goto, Takeshi Kikuchi, Teppei Okabe, Yoshiaki Hasegawa, Yoshihiko Sugita, Hirotaka Fujitsuka, Ryosuke Kataoka, Koudai Katsumata, Ryoma Goto, Yuiko Suzuki, Jun-Ichiro Hayashi, Masayuki Umemura, Akio Mitani

{"title":"IL-35 May Prevent the Exacerbation of Aspiration Pneumonia Involving Porphyromonas gingivalis by Suppressing IL-17 Production.","authors":"Shotaro Kawamura, Hisashi Goto, Takeshi Kikuchi, Teppei Okabe, Yoshiaki Hasegawa, Yoshihiko Sugita, Hirotaka Fujitsuka, Ryosuke Kataoka, Koudai Katsumata, Ryoma Goto, Yuiko Suzuki, Jun-Ichiro Hayashi, Masayuki Umemura, Akio Mitani","doi":"10.1016/j.ajpath.2024.11.009","DOIUrl":"10.1016/j.ajpath.2024.11.009","url":null,"abstract":"Periodontitis was reported to be associated with aspiration pneumonia. However, the relationship between periodontitis and aspiration pneumonia remains unclear. This study investigated the virulence factor of Porphyromonas gingivalis, which exacerbates aspiration pneumonia, and the role of IL-35, an inhibitory heterodimeric cytokine of EBI3 and p35, in aspiration pneumonia using Ebi3 knockout (KO) mice. Aspiration pneumonia was induced by the intratracheal injection of Streptococcus pneumoniae and P. gingivalis culture supernatant (mixed infection). We used leupeptin to inhibit gingipain, a virulence factor of P. gingivalis. Four days after infection, lung tissues were collected for analyses. The percentage of interstitium in the group with mixed infection and leupeptin treatment was significantly reduced compared with the nonleupeptin administration group. Additionally, the percentage of interstitium in the field of Ebi3 KO mice was significantly increased compared with wild-type (WT) mice in mixed infection. IL-35 production in WT mice with mixed infection was significantly increased compared with the control group. IL-17 production in Ebi3 KO mice was significantly increased compared with WT mice with mixed infection. These findings suggest that gingipain exacerbates aspiration pneumonia and that IL-35 may contribute to suppressing the exacerbation of aspiration pneumonia.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891616","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

P46Shc Inhibits Mitochondrial ACAA2 Thiolase, Exacerbating Mitochondrial Injury and Inflammation in Aging Livers.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-20 DOI: 10.1016/j.ajpath.2024.10.022

Yuan Li, Weiguo Fan, Tzu-Han Lo, Joy X Jiang, Sarah R Fish, Alexey Tomilov, Antonios Chronopoulos, Vidushi Bansal, Gergely Mozes, Lorand Vancza, Koshi Kunimoto, Jiayu Ye, Laren Becker, Suvarthi Das, Hyesuk Park, Yi Wei, Sara Ranjbarvaziri, Daniel Bernstein, Jon Ramsey, Gino Cortopassi, Natalie J Török

{"title":"P46Shc Inhibits Mitochondrial ACAA2 Thiolase, Exacerbating Mitochondrial Injury and Inflammation in Aging Livers.","authors":"Yuan Li, Weiguo Fan, Tzu-Han Lo, Joy X Jiang, Sarah R Fish, Alexey Tomilov, Antonios Chronopoulos, Vidushi Bansal, Gergely Mozes, Lorand Vancza, Koshi Kunimoto, Jiayu Ye, Laren Becker, Suvarthi Das, Hyesuk Park, Yi Wei, Sara Ranjbarvaziri, Daniel Bernstein, Jon Ramsey, Gino Cortopassi, Natalie J Török","doi":"10.1016/j.ajpath.2024.10.022","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.10.022","url":null,"abstract":"Mitochondrial maladaptation and dysfunction contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH). The authors recently implicated the induction of Shc in progressive MASH during aging and the cytoplasmic p52Shc isoform in the activation of redox enzyme NOX2. The mitochondrial Shc isoform p46Shc was shown to repress acetyl-coenzyme A acyltransferase 2 (ACAA2) in vitro. ACAA2 is a key enzyme for lipid β-oxidation; however, the metabolic consequences of in vivo p46Shc induction were unknown. The authors generated p46Shc-inducible mice; these and littermate controls were aged and fed chow or fast-food diet (high-fat and high-fructose). p46Shc induction increased liver injury, inflammation, and lipid peroxidation. p46Shc overexpression did not significantly change liver triglycerides. On electron microscopy studies, mitochondria were swollen with aberrant cristae. p46Shc induction reduced mitochondrial oxygen consumption as measured by Oroboros, as well as suppressed the production of β-hydroxybutyrate, the central metabolite of therapeutic ketosis. Mitochondria exhibited increased production of reactive oxidative species. By contrast, the expression of dominant negative p46Shc reduced ACAA2 thiolase activity, improved β-oxidation, and reduced lipid peroxidation and production of reactive oxidative species. In summary, these studies support the concept that p46Shc induction in aging represses ACAA2, resulting in decreased mitochondrial β-oxidation and increased lipid peroxidation. Maintaining β-oxidation and ketogenesis could prevent liver injury, and targeting Shc-related maladaptive responses could be a successful therapeutic strategy in aging/MASH.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902597","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

Ablation of Hepatic Asah1 Gene Disrupts Hepatic Lipid Homeostasis and Promotes Fibrotic Nonalcoholic Steatohepatitis in Mice.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-20 DOI: 10.1016/j.ajpath.2024.11.003

Rui Zuo, Mi Wang, Yun-Ting Wang, YangPing ShenTu, Alexandra K Moura, Ying Zhou, Kiana Roudbari, Jenny Z Hu, Pin-Lan Li, JiuKuan Hao, Xiang Li, Yang Zhang

{"title":"Ablation of Hepatic Asah1 Gene Disrupts Hepatic Lipid Homeostasis and Promotes Fibrotic Nonalcoholic Steatohepatitis in Mice.","authors":"Rui Zuo, Mi Wang, Yun-Ting Wang, YangPing ShenTu, Alexandra K Moura, Ying Zhou, Kiana Roudbari, Jenny Z Hu, Pin-Lan Li, JiuKuan Hao, Xiang Li, Yang Zhang","doi":"10.1016/j.ajpath.2024.11.003","DOIUrl":"10.1016/j.ajpath.2024.11.003","url":null,"abstract":"Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of chronic liver conditions, ranging from simple steatosis to nonalcoholic steatohepatitis, which may progress to fibrosis/cirrhosis. Here, the GSE163211 data set was analyzed, and Asah1 (encoding acid ceramidase) was identified as a crucial lysosomal gene that positively correlated with NAFLD stages in obese patients. To evaluate the role of Asah1 in the progression of NAFLD, Asah1fl/fl/Albcre mice (hepatocyte-specific deletion of Asah1) and Asah1 floxed (Asah1fl/fl/wild-type) mice were fed with either a normal diet or a high-fat, high-cholesterol paigen diet (PD) for 20 weeks. The results showed that hepatocyte-specific Asah1 ablation markedly aggravated PD-induced hepatic steatosis, hepatitis, and apoptosis, and resulted in marked fibrotic changes. In addition, Asah1 gene ablation exacerbated PD-induced portal venous hemodynamic abnormality. In cultured hepatocytes, Asah1 gene knockdown resulted in increased ceramide and cholesterol levels but did not affect triglyceride level. Knocking down Asah1 gene also exhibited broad impacts on lipid homeostasis pathways, including lipogenesis, fatty acid uptake, fatty acid oxidation, and lipid transport. Furthermore, Asah1 knockdown resulted in increased endoplasmic reticulum stress and lipid droplet biogenesis. Last, Asah1 gene knockdown impaired chaperone-mediated autophagy. In conclusion, these results suggest that Asah1 functions as an important regulator of hepatic lipid homeostasis, and its deficiency exacerbates hepatocyte lipotoxicity and injury, and promotes the development of fibrotic nonalcoholic steatohepatitis.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884868","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

Cholangiocarcinoma Targeted Therapies: Mechanisms of Action and Resistance.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-19 DOI: 10.1016/j.ajpath.2024.11.005

Haley Ellis, Chiara Braconi, Juan W Valle, Nabeel Bardeesy

{"title":"Cholangiocarcinoma Targeted Therapies: Mechanisms of Action and Resistance.","authors":"Haley Ellis, Chiara Braconi, Juan W Valle, Nabeel Bardeesy","doi":"10.1016/j.ajpath.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.11.005","url":null,"abstract":"Cholangiocarcinoma is an aggressive bile duct malignancy with heterogeneous genomic features. Although most patients receive standard-of-care chemotherapy/immunotherapy, genomic changes that can be targeted with established or emerging therapeutics are common. Accordingly, precision medicine strategies are transforming the next-line treatment for patient subsets. Hotspot IDH1 mutations and activating fibroblast growth factor receptor 2 fusions occur frequently, and small-molecule inhibitors against these alterations are US Food and Drug Administration approved. Translational and basic science studies have elucidated the mechanisms of response and resistance in cholangiocarcinoma, providing insights into these targets that extend to other cancers. Additional US Food and Drug Administration-approved and National Comprehensive Cancer Network guideline-recommended treatments for recurrent genomic changes include BRAF inhibition (BRAF-V600E) and trastumazab deruxtecan (human epidermal growth factor receptor 2 amplification). Furthermore, ongoing clinical trials show promising results with KRAS inhibition (KRAS-codon 12 mutations), PRTM5 inhibition, alone or with methylthioadenosine inhibition (5-methylthioadenosine phosphorylase deletion), and murine double minute 2 inhibition (murine double minute 2 amplification). Despite these advances, the rate, depth, and duration of response to each treatment need improvement. Moreover, many patients do not have currently targetable genotypes. In this review, we examine the clinical efficacy and mechanisms of resistance associated with these treatments, as well as insights into the molecular and biological effects of pathway activation and inhibition, based on study of patient samples and preclinical models. We also explore strategies to overcome resistance and possible precision medicine approaches for additional patient subsets.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891603","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

Gut Microbiome and Bile Acid Interactions: Mechanistic Implications for Cholangiocarcinoma Development, Immune Resistance, and Therapy.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-19 DOI: 10.1016/j.ajpath.2024.11.004

Nan Wu, Sareh Bayatpour, Phillip B Hylemon, Sayed Obaidullah Aseem, Paul J Brindley, Huiping Zhou

{"title":"Gut Microbiome and Bile Acid Interactions: Mechanistic Implications for Cholangiocarcinoma Development, Immune Resistance, and Therapy.","authors":"Nan Wu, Sareh Bayatpour, Phillip B Hylemon, Sayed Obaidullah Aseem, Paul J Brindley, Huiping Zhou","doi":"10.1016/j.ajpath.2024.11.004","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.11.004","url":null,"abstract":"Cholangiocarcinoma (CCA) is a rare but highly malignant carcinoma of bile duct epithelial cells with a poor prognosis. The major risk factors of CCA carcinogenesis and progression are cholestatic liver diseases. The key feature of primary sclerosing cholangitis and primary biliary cholangitis is chronic cholestasis, which means a slowdown of hepatocyte secretion of biliary lipids and metabolites into bile as well as a slowdown of enterohepatic circulation (bile acid recirculation) of bile acids with dysbiosis of the gut microbiome, which was shown to lead to enterohepatic recirculation and an increase of toxic secondary bile acids. Alterations of serum and liver bile acid compositions via the disturbed enterohepatic circulation of bile acids and the disturbance of the gut microbiome then activate a series of hepatic and cancer cell signaling pathways that promote CCA carcinogenesis and progression. This review will focus on the mechanistic roles of bile acids and the gut microbiome in the pathogenesis and progression of CCA. We will also evaluate the therapeutic potential of targeting the gut microbiome and bile acid-mediated signaling pathways for the therapy and prophylaxis of CCA.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891613","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

Genetically Engineered Mouse Models for Alzheimer Disease and Frontotemporal Dementia: New Insights from Single-Cell and Spatial Transcriptomics.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-19 DOI: 10.1016/j.ajpath.2024.11.006

Yuanpu Chiu, Shangzhou Xia, Haowen Qiao, Zhen Zhao

引用次数: 0

Development of CAR-T Therapies and Personalized Vaccines for the Treatment of Cholangiocarcinoma: Current Progress, Mechanisms of Action, and Challenges. 开发用于治疗胆管癌的 CAR-T 疗法和个性化疫苗：当前进展、作用机制和挑战。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-14 DOI: 10.1016/j.ajpath.2024.10.021

Dan Li, Lalitya Andaloori, Matthew Crowe, Shaoli Lin, Jessica Hong, Neeha Zaidi, Mitchell Ho

{"title":"Development of CAR-T Therapies and Personalized Vaccines for the Treatment of Cholangiocarcinoma: Current Progress, Mechanisms of Action, and Challenges.","authors":"Dan Li, Lalitya Andaloori, Matthew Crowe, Shaoli Lin, Jessica Hong, Neeha Zaidi, Mitchell Ho","doi":"10.1016/j.ajpath.2024.10.021","DOIUrl":"10.1016/j.ajpath.2024.10.021","url":null,"abstract":"Cholangiocarcinoma (CCA) is a highly fatal malignancy with an increasing prevalence, a high mortality rate, poor overall survival, and limited responsiveness to conventional chemoradiotherapy. Targeted therapies addressing specific gene mutations have expanded treatment options for some patient populations. The introduction of chimeric antigen receptor-modified T-cell (CAR-T) immunotherapy and personalized vaccines have opened up a new avenue for managing various cancers. Considerable efforts have been dedicated to preclinical research and ongoing clinical trials of immunotherapeutic approaches including CAR-T therapy, vaccines, and antibody-based therapies such as antibody drug conjugates. However, the potential of CAR-T therapy and vaccines in treating advanced unresectable/metastatic cholangiocarcinoma remains largely unexplored. This article offers an overview of the current landscape of antibody-based immunotherapy, particularly CAR-T therapy and vaccines in the context of cholangiocarcinoma treatment. It outlines a framework for selecting CAR-T and vaccine targets and delves into the biology of promising targetable antigens, as well as potential future therapeutic targets.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827015","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