Fibroblast Activation
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2021 ◽  
pp. jnumed.121.262863
Meiqi Wu ◽  
Jing Ning ◽  
Jingle Li ◽  
Zhichao Lai ◽  
Ximin Shi ◽  

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257195
Tim Muilwijk ◽  
Murat Akand ◽  
Sofie Daelemans ◽  
Koen Marien ◽  
Yannick Waumans ◽  

Fibroblast activation protein-α (FAP) is a transmembrane peptidase and a surrogate marker for cancer-associated fibroblasts (CAFs). FAP has been linked to worse prognosis and therapy resistance in several cancers. We hypothesised that FAP might have a prognostic 3biomarker potential to stratify patients with high-grade (HG) T1 non-muscle-invasive bladder cancer (NMIBC). We selected 30 patients with HG T1 NMIBC that progressed to ≥T2 disease which were pair-matched based on CUETO progression score variables with 90 patients that did not progress. After revision a final cohort of 86 patients was retained. Slides were stained for FAP, the luminal marker GATA3 and the basal marker CK5. All HG T1 tumour regions of interest (ROIs) within each patient were annotated, analysed and scored using image analysis software. FAP expression in HG T1 ROIs was significantly higher in progressors vs. non-progressors and was prognostic for recurrence-free survival, progression-free survival, cancer-specific survival, and overall survival. FAP expression in HG T1 ROIs remained strongly prognostic for these outcomes in a bivariable model corrected for adequate BCG per FDA definition. Expression of GATA3 and CK5 did not differ between progressors vs. non-progressors, and were not prognostic for these outcomes. FAP might serve as an easily applicable prognostic biomarker to risk-stratify patients with HG T1 NMIBC if these results are prospectively validated in a larger series.

2021 ◽  
Vol 28 ◽  
Xing-Kai Qian ◽  
Jing Zhang ◽  
Xiao-Dong Li ◽  
Pei-Fang Song ◽  
Li-Wei Zou

: Prolyl-specific peptidases or proteases, including Dipeptidyl Peptidase 2, 4, 6, 8, 9, 10, Fibroblast Activation Protein, prolyl endopeptidase and prolyl carboxypeptidase, belong to the dipeptidyl peptidase family. In human physiology and anatomy, they have homology amino acid sequences, similarities in structure, but play distinct functions and roles. Some of them also play important roles in the metabolism of drugs containing endogenous peptides, xenobiotics containing peptides, and exogenous peptides. The major functions of these peptidases in both the metabolism of human health and bioactive peptides are of significant importance in the development of effective inhibitors to control the metabolism of endogenous bioactive peptides. The structural characteristics, distribution of tissue, endogenous substrates, and biological functions were summarized in this review. Furthermore, the xenobiotics metabolism of the dipeptidyl peptidase family is illustrated. All the evidence and information summarized in this review would be very useful for researchers to extend the understanding of the proteins of these families and offer advice and assistance in physiology and pathology studies.

JCI Insight ◽  
2021 ◽  
Prathibha R. Gajjala ◽  
Rajesh K. Kasam ◽  
Divyalakshmi Soundararajan ◽  
Debora Sinner ◽  
Steven K. Huang ◽  

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2412
Prachi Umbarkar ◽  
Suma Ejantkar ◽  
Sultan Tousif ◽  
Hind Lal

Heart failure (HF) is a leading cause of morbidity and mortality across the world. Cardiac fibrosis is associated with HF progression. Fibrosis is characterized by the excessive accumulation of extracellular matrix components. This is a physiological response to tissue injury. However, uncontrolled fibrosis leads to adverse cardiac remodeling and contributes significantly to cardiac dysfunction. Fibroblasts (FBs) are the primary drivers of myocardial fibrosis. However, until recently, FBs were thought to play a secondary role in cardiac pathophysiology. This review article will present the evolving story of fibroblast biology and fibrosis in cardiac diseases, emphasizing their recent shift from a supporting to a leading role in our understanding of the pathogenesis of cardiac diseases. Indeed, this story only became possible because of the emergence of FB-specific mouse models. This study includes an update on the advancements in the generation of FB-specific mouse models. Regarding the underlying mechanisms of myocardial fibrosis, we will focus on the pathways that have been validated using FB-specific, in vivo mouse models. These pathways include the TGF-β/SMAD3, p38 MAPK, Wnt/β-Catenin, G-protein-coupled receptor kinase (GRK), and Hippo signaling. A better understanding of the mechanisms underlying fibroblast activation and fibrosis may provide a novel therapeutic target for the management of adverse fibrotic remodeling in the diseased heart.

Phung N. Thai ◽  
Lu Ren ◽  
Wilson Xu ◽  
James Overton ◽  
Valeriy Timofeyev ◽  

Abstract Purpose Nonsteroidal anti-inflammatory drugs (NSAIDs) are among one of the most commonly prescribed medications for pain and inflammation. Diclofenac (DIC) is a commonly prescribed NSAID that is known to increase the risk of cardiovascular diseases. However, the mechanisms underlying its cardiotoxic effects remain largely unknown. In this study, we tested the hypothesis that chronic exposure to DIC increases oxidative stress, which ultimately impairs cardiovascular function. Methods and Results Mice were treated with DIC for 4 weeks and subsequently subjected to in vivo and in vitro functional assessments. Chronic DIC exposure resulted in not only systolic but also diastolic dysfunction. DIC treatment, however, did not alter blood pressure or electrocardiographic recordings. Importantly, treatment with DIC significantly increased inflammatory cytokines and chemokines as well as cardiac fibroblast activation and proliferation. There was increased reactive oxygen species (ROS) production in cardiomyocytes from DIC-treated mice, which may contribute to the more depolarized mitochondrial membrane potential and reduced energy production, leading to a significant decrease in sarcoplasmic reticulum (SR) Ca2+ load, Ca2+ transients, and sarcomere shortening. Using unbiased metabolomic analyses, we demonstrated significant alterations in oxylipin profiles towards inflammatory features in chronic DIC treatment. Conclusions Together, chronic treatment with DIC resulted in severe cardiotoxicity, which was mediated, in part, by an increase in mitochondrial oxidative stress.

2021 ◽  
Kongzhen Hu ◽  
Lijuan Wang ◽  
Hubing Wu ◽  
Shun Huang ◽  
Ying Tian ◽  

Abstract Purpose: [18F]FAPI-42 is a new fibroblast activation protein (FAP) specific tracer used for cancer imaging. Here, we describe the in vivo evaluation of [18F]FAPI-42 and compared intra-individual biodistribution, tumor uptake, and detection ability to [68Ga]Ga-FAPI-04.Methods: A total of 22 patients with various types of cancer received [18F]FAPI-42 whole-body positron emission tomography/computed tomography (PET/CT). Among them, 4 patients underwent PET/CT scans, including an early dynamic 20-min, static 1-hour and static 2-hours. The in vivo biodistribution in normal organs and tumor uptake were semi-quantitatively evaluated using the standardized uptake value (SUV) and tumor-to-background ratio (TBR). Furthermore, both [18F]FAPI-42 and [68Ga]Ga-FAPI-04 PET/CT were performed in 12 patients to compare biodistribution, tumor uptake, and tumor detection ability.Results: [18F]FAPI-42 uptake in the tumors was rapid and reached a high level with an average SUVmax of 15.8 at 18 minutes, which stayed at a similarly high level to 2 hours. The optimal image acquisition time for [18F]FAPI-42 was determined to be 1 hour post injection. Compared to [68Ga]Ga-FAPI-04, [18F]FAPI-42 had a higher uptake in the parotid, salivary gland, thyroid, and pancreas (P < 0.05). For tumor detection, [18F]FAPI-42 had a high uptake and could be clearly visualized in the lesions. [18F]FAPI-42 and [68Ga]Ga-FAPI-04 showed the same detectability for 144 positive lesions. In addition, [18F]FAPI-42 had a higher SUVmax in liver and bone lesions (P < 0.05) and higher TBRs in liver, bone, lymph node, pleura and peritonea lesions (all P < 0.05).Conclusion: The present study demonstrates that [18F]FAPI-42 is a good tracer for imaging malignant tumors and exhibited comparable lesion detectability to [68Ga]Ga-FAPI-04. The 1-hour scan is an appropriate time for tumor detection and is superior to the early 10-min scan for the detection of small lesions.Trial registration Chinese Clinical Trial Registry (ChiCTR2100045757)

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