A Case of Squamous Cell Carcinoma Arising in Disseminated Superficial Porokeratosis.

Porokeratosis (PK), characterized by keratotic lesions with an atrophic center and a prominent peripheral ridge, with a typical histological hallmark, namely, the cornoid lamella, has two forms: disseminated and localized. While PK often converts into squamous cell carcinoma (SCC), conversion from disseminated superficial porokeratosis (DSP) alone is rarely reported except for one case in which DSP and LP coexisted and converted to SCC. Here, we report the case of a patient with SCC converted from DSP alone, presenting with coin-sized macules on the bottom right of his waist that developed into an ulcer at the center. The patient underwent radiation therapy, which effectively treated the SCC but did not resolve the PK. This article highlights regular follow-up and undergo comprehensive diagnosis, both of which are beneficial to enable early detection and management of DSP that has converted to into SCC; in addition, standardized medical treatment may help improve the treatment therapeutic effect of in similar diseases.

Real-world persistence of multiple sclerosis disease-modifying therapies.

BACKGROUND AND PURPOSE: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.

Expression and functional significance of phosphoenolpyruvate carboxykinase 1 in uveal melanoma.

Uveal melanoma (UVM), an uncommon yet potentially life-threatening ocular cancer, arises from melanocytes in the uveal tract of the eye. The exploration of novel oncotargets for UVM is of paramount importance. In this study, we show that PCK1 (phosphoenolpyruvate carboxykinase 1) expression is upregulated in various UVM tissues as well as in primary UVM cells and immortalized lines. Furthermore, bioinformatics studies reveal that PCK1 overexpression in UVM correlates with advanced disease stages and poor patient survival. Genetic silencing (utilizing viral shRNA) or knockout (via CRISPR/Cas9) of PCK1 significantly curtailed cell viability, proliferation, cell cycle progression, and motility, while provoking apoptosis in primary and immortalized UVM cells. Conversely, ectopic overexpression of PCK1, achieved through a viral construct, bolstered UVM cell proliferation and migration. Gαi3 expression and Akt phosphorylation were reduced following PCK1 silencing or knockout, but increased after PCK1 overexpression in UVM cells. Restoring Akt phosphorylation through a constitutively active mutant Akt1 (S473D) ameliorated the growth inhibition, migration suppression, and apoptosis induced by PCK1 silencing in UVM cells. Additionally, ectopic expression of Gαi3 restored Akt activation and counteracted the anti-UVM cell effects by PCK1 silencing. In vivo, the growth of subcutaneous xenografts of primary human UVM cells was significantly inhibited following intratumoral injection of adeno-associated virus (aav) expressing PCK1 shRNA. PCK1 depletion, Gαi3 downregulation, Akt inhibition, proliferation arrest, and apoptosis were detected in PCK1-silenced UVM xenografts. Collectively, our findings demonstrate that PCK1 promotes UVM cell growth possibly by modulating the Gαi3-Akt signaling pathway.

Influence of voluntary action and outcome valence on the sense of agency.

Recent studies have revealed that people might experience a lessened sense of agency for negative consequences by claiming that they were obeying orders. However, little is known about the cognitive neural mechanism behind the reduced sense of agency when individuals are forced to inflict physical harm on others. This study adopted temporal estimation tasks to investigate the internal mechanism of voluntary action on the sense of agency and the moderating effect of outcome valence as measured by event-related potentials (ERPs). In the temporal estimation task, participants were asked to make trade-offs of monetary gains for themselves against painful electric stimuli experienced by strangers, subjectively estimated the perceptual temporal interval between keypress actions (i.e., free or coercive actions) and consequent outcomes (i.e., positive or negative tones) and rated the feeling of control. The results showed that perceived temporal interval was shorter for positive tones compared with negative tones in the coercive condition, and induced more negative N1 and N300 amplitudes, which indicated that the implicit sense of agency was higher. However, the explicit sense of agency was stronger in the free condition than in the coercive condition, which was not influenced by outcome valence. We discuss the implications of utilizing positive feedback and free choice as significant strategies for those experiencing the abnormal sense of agency.

Comparative Study on Chemical Constituents of Ginseng Flowers with Four Consecutive Cultivation Age.

The harvest period of cultivated ginseng is generally 4-6 years. Ginseng flowers (GFs), the nonmedicinal parts, are usually removed every autumn, in which components are generally believed to stay unchanged with the increasing cultivation age. Recently, few documents were reported on the variation of volatile organic compounds (VOCs) and other components about ginseng flowers. This study had an insight into the variation of the chemical constituents with the cultivation ages through the comparison of the volatile organic compounds, gross ginsenosides, crude polysaccharide, and gross proteins of ginseng flowers from 3-, 4-, 5-, and 6-yr-old (GF3, GF4, GF5, and GF6) which were conducted by headspace solid-phase microextraction-gas chromatography-triple quadrupole mass spectrometry (HS-SPME-GC-QQQ/MS) and spectroscopic analysis combined with multivariate statistical analysis, including one-way ANOVA analysis and T test. The results indicated that the crude polysaccharide contents raised significantly depending on cultivation age except 6-yr-old, whereas the gross ginsenosides and the gross protein content were indistinctive. According to the peak intensity of determined VOCs, the contents of most differential compounds arranged in an order from high to low are GF3, GF4, GF5, and GF6, such as the compounds 2-15, 17-19, 22, and 25-26, therefore, they can be inferred that they are important markers to identify the age of GFs. 461 common differential compounds were gained and 26 common volatile organic compounds were identified with RSI >800 and RI and RIx no more than 30, including alcohols (such as 11, 12, and 15), sesquiterpenes (such as 2, 3, and 4), esters (such as 1 and 26), naphthalene and naphthol (such as 7 and 20), which had potential effects on curing Alzheimer's disease, inflammatory diseases, and prostate cancer based on network pharmacology analysis. This paper firstly revealed the variation rules of constitutions of GFs, which may provide a reference for the harvest and making rational application.

Identification and Characterisation of Infiltrating Immune Cells in Malignant Pleural Mesothelioma Using Spatial Transcriptomics.

Increasing evidence strongly supports the key role of the tumour microenvironment in response to systemic therapy, particularly immune checkpoint inhibitors (ICIs). The tumour microenvironment is a complex tapestry of immune cells, some of which can suppress T-cell immunity to negatively impact ICI therapy. The immune component of the tumour microenvironment, although poorly understood, has the potential to reveal novel insights that can impact the efficacy and safety of ICI therapy. Successful identification and validation of these factors using cutting-edge spatial and single-cell technologies may enable the development of broad acting adjunct therapies as well as personalised cancer immunotherapies in the near future. In this paper we describe a protocol built upon Visium (10x Genomics) spatial transcriptomics to map and characterise the tumour-infiltrating immune microenvironment in malignant pleural mesothelioma. Using ImSig tumour-specific immune cell gene signatures and BayesSpace Bayesian statistical methodology, we were able to significantly improve immune cell identification and spatial resolution, respectively, improving our ability to analyse immune cell interactions within the tumour microenvironment.

By-Product of the Red Ginseng Manufacturing Process as Potential Material for Use as Cosmetics: Chemical Profiling and In Vitro Antioxidant and Whitening Activities.

Red ginseng (RG), which is obtained from heated Panax ginseng and is produced by steaming followed by drying, is a valuable herb in Asian countries. Steamed ginseng dew (SGD) is a by-product produced in processing red ginseng. In the present study, phytochemical profiling of extracts of red ginseng and steamed ginseng dew was carried out using gas chromatography-mass spectrometry (GC-MS) and rapid resolution liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (RRLC-Q-TOF-MS) analysis. Additionally, antioxidant activities (DPPH, ·OH, and ABTS scavenging ability) and whitening activities (tyrosinase and elastase inhibitory activity) were analyzed. Phytochemical profiling revealed the presence of 66 and 28 compounds that were non-saponin components in chloroform extracts of red ginseng and steamed ginseng dew (RG-CE and SGD-CE), respectively. Meanwhile, there were 20 ginsenosides identified in n-butanol extracts of red ginseng and steamed ginseng dew (RG-NBE and SGD-NBE). By comparing the different polar extracts of red ginseng and steamed ginseng dew, it was found that the ethyl acetate extract of red ginseng (RG-EAE) had the best antioxidant capacity and whitening effect, the water extract of steamed ginseng dew (SGD-WE) had stronger antioxidant capacity, and the SGD-NBE and SGD-CE had a better whitening effect. This study shows that RG and SGD have tremendous potential to be used in the cosmetic industries.

Tumor cell-derived asymmetric dimethylarginine regulates macrophage functions and polarization.

BACKGROUND: Asymmetric dimethylarginine (ADMA), which is significantly elevated in the plasma of cancer patients, is formed via intracellular recycling of methylated proteins and serves as a precursor for resynthesis of arginine. However, the cause of ADMA elevation in cancers and its impact on the regulation of tumor immunity is not known. METHODS: Three mouse breast cell lines (normal breast epithelial HC11, breast cancer EMT6 and triple negative breast cancer 4T1) and their equivalent 3D stem cell culture were used to analyze the secretion of ADMA using ELISA and their responses to ADMA. Bone marrow-derived macrophages and/or RAW264.7 cells were used to determine the impact of increased extracellular ADMA on macrophage-tumor interactions. Gene/protein expression was analyzed through RNAseq, qPCR and flow cytometry. Protein functional analyses were conducted via fluorescent imaging (arginine uptake, tumor phagocytosis) and enzymatic assay (arginase activity). Cell viability was measured via MTS assay and/or direct cell counting using Countess III FL system. RESULTS: For macrophages, ADMA impaired proliferation and phagocytosis of tumor cells, and even caused death in cultures incubated without arginine. ADMA also led to an unusual macrophage phenotype, with increased expression of arginase, cd163 and cd206 but decreased expression of il10 and dectin-1. In contrast to the severely negative impacts on macrophages, ADMA had relatively minor effects on proliferation and survival of mouse normal epithelial HC11 cells, mouse breast cancer EMT6 and 4T1 cells, but there was increased expression of the mesenchymal markers, vimentin and snail2, and decreased expression of the epithelial marker, mucin-1 in EMT6 cells. When tumor cells were co-cultured ex vivo with tumor antigen in vivo-primed splenocytes, the tumor cells secreted more ADMA and there were alterations in the tumor cell arginine metabolic landscape, including increased expression of genes involved in arginine uptake, metabolism and methylation, and decreased expression of a gene that is responsible for arginine demethylation. Additionally, interferon-gamma, a cytokine involved in immune challenge, increased secretion of ADMA in tumor cells, a process attenuated by an autophagy inhibitor. CONCLUSION: Our results suggest initial immune attack promotes autophagy in tumor cells, which then secrete ADMA to manipulate macrophage polarization favoring tumor tolerance.

Environmental Protection or Self-Interest? The Public Accountability Moderates the Effects of Materialism and Advertising Appeals on the Pro-Environmental Behavior.

Background: Previous studies have examined the negative effects of materialism, which refers to the importance of possessing material wealth and image, on the pro-environmental behavior. Recently, a study found that highly materialistic individuals showed more pro-environmental behaviors involving self-benefit (vs other-benefit) appeals. However, previous studies ignored the role of public accountability. Purpose: This study aimed to explore the relationship between advertising appeals and the pro-environmental behavior of materialistic individuals in public (vs private) situations. Methods: This study used the material values scale to measure the materialistic extent and employed different advertising pictures. Meanwhile, Study 1(N=593) used the public cue, and Study 2 (N=622) used the eye cue to manipulate public accountability. Environmental donation was an indicator of the pro-environmental behavior. Results: Studies 1 and 2 found that the pro-environmental behavior of participants low in materialism was significantly higher than that of participants high in materialism involving other-benefit appeals, while this difference was not significant for pro-environmental behavior involving self-benefit appeals in the private situation. Participants with low and high materialism were not significantly different in the pro-environmental behavior involving self-benefit and other-benefit appeals in the public situation. Conclusion: The relationship between materialism and pro-environmental behavior involving self-benefit and other-benefit appeals can be moderated by the public accountability. In the private context, self-benefit appeals led materialistic people to engage in more pro-environmental behavior, while in the public context, the effectiveness of self-benefit and other-benefit appeals on the pro-environmental behavior of materialistic individuals was similar.

Improved risk stratification of nasopharyngeal cancer by targeted sequencing of Epstein-Barr virus DNA in post-treatment plasma.

BACKGROUND: Quantitative measurement of plasma Epstein-Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients. PATIENTS AND METHODS: Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA. RESULTS: The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS. CONCLUSION: NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing.

In Situ Assembly of Transmembrane Proteins from Expressed and Synthetic Components in Giant Unilamellar Vesicles.

Reconstituting functional transmembrane (TM) proteins into model membranes is challenging due to the difficulty of expressing hydrophobic TM domains, which often require stabilizing detergents that can perturb protein structure and function. Recent model systems solve this problem by linking the soluble domains of membrane proteins to lipids, using noncovalent conjugation. Herein, we test an alternative solution involving the in vitro assembly of TM proteins from synthetic TM domains and expressed soluble domains using chemoselective peptide ligation. We developed an intein mediated ligation strategy to semisynthesize single-pass TM proteins in synthetic giant unilamellar vesicle (GUV) membranes by covalently attaching soluble protein domains to a synthetic TM polypeptide, avoiding the requirement for detergent. We show that the extracellular domain of programmed cell death protein 1, a mammalian immune checkpoint receptor, retains its ligand-binding function at a membrane interface after ligation to a synthetic TM peptide in GUVs, facilitating the study of receptor-ligand interactions.

Interpersonal distance modulates the influence of social observation on prosocial behaviour: An event-related potential (ERP) study.

This study aimed to explore the influence of interpersonal distance and social observation on prosocial behaviour. Participants were instructed to make costly prosocial decisions towards different interpersonal distance targets (friends, acquaintances or strangers) under the (non) observable condition, with simultaneous electroencephalogram recording. The behavioural results demonstrated that participants made more prosocial choices-unaffected by social observation-towards friends than towards acquaintances and strangers; nonetheless, participants made more prosocial choices towards acquaintances and strangers under the observable than under the non-observable condition. Event-related potential results showed that when participants made prosocial decisions towards friends, the P3 and N2 amplitudes remained unchanged between the observable and non-observable conditions; however, when participants made prosocial decisions towards acquaintances and strangers, a smaller N2 and a larger P3 were observed under the observable than those under the non-observable condition. These findings suggest that prosocial behaviour towards friends is driven by social preferences regarding the welfare of others, regardless of the possibility of reputation management. However, prosocial behaviour towards acquaintances and strangers might be motivated by a positive reputation, because individuals may bear in mind the potential future benefits.

Update on the Recommendations on Breast Cancer Screening by the Cancer Expert Working Group on Cancer Prevention and Screening.

Breast cancer (BC) is the most common cancer among women in Hong Kong. The Food and Health Bureau commissioned The University of Hong Kong (HKU) to conduct the Hong Kong Breast Cancer Study (HKBCS) with the aim of identifying relevant risk factors for BC in Hong Kong and developing a locally validated BC risk assessment tool for Hong Kong Chinese women. After consideration of the most recent international and local scientific evidence including findings of the HKBCS, the Cancer Expert Working Group on Cancer Prevention and Screening (CEWG) has reviewed and updated its BC screening recommendations. Existing recommendations were preserved for women at high risk and slightly changed for women at moderate risk. The following major updates have been made concerning recommendations for other women in the general population: Women aged 44 to 69 with certain combinations of personalised risk factors (including presence of history of BC among first-degree relative, a prior diagnosis of benign breast disease, nulliparity and late age of first live birth, early age of menarche, high body mass index and physical inactivity) putting them at increased risk of BC are recommended to consider mammography screening every 2 years. They should discuss with their doctors on the potential benefits and harms before undergoing mammography screening. A risk assessment tool for local women (eg, one developed by HKU) is recommended to be used for estimating the risk of developing BC with regard to the personalised risk factors described above.

Exposure to money modulates the processing of charitable donation: An event-related potentials study.

Exposure to monetary cues might affect charitable donations, but little is known about how monetary cues affect charitable donations from the neural perspective. The present study examined the effect of monetary cues on charitable donations by means of event-related potentials (ERPs). Participants primed with monetary or neutral images decided whether to accept donation offers with the high, moderate, and low costs. The behavioural results showed that in the money-primed condition, participants took more time to decide for the high-cost than for the moderate and low-cost donation offers. The ERP results showed that the P2 and P3 were larger in the money-primed condition relative to the neutral images condition. Notably, participants primed with money demonstrated larger P3 for the high-cost donation offers than for the moderate and low-cost offers, but this difference was not observed in the control condition. These findings indicate that people primed with money may pay more attention to the cost-relevant information related to their self-interests when conducting prosocial behaviours.

Simultaneous Quantification of Four Ginsenosides in Rat Plasma and Its Application to a Comparative Pharmacokinetic Study in Normal and Depression Rats Using UHPLC-MS/MS.

A sensitive method has been developed for simultaneous determination of ginsenoside Rh1 (G-Rh1), ginsenoside Rb1 (G-Rb1), ginsenoside Rc (G-Rc), and ginsenoside Rd (G-Rd) in rat plasma of normal and depression model group after oral administration of their solutions by using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-QQQ-MS). The biological samples were prepared by protein precipitation. Ginsenoside Rg3 (G-Rg3) was used as an internal standard (IS). MS analysis was performed under the multiple reaction monitoring (MRM) with electron spray ionization (ESI) operated in the negative mode. The method showed good linearity over a wide concentration range (R 2 > 0.999) and obtained lower limits of quantification (LLOQ) of 5 ng/mL. The whole analysis procedure could be completed in as short as 16.5 min. The intraday precisions, interday precisions, and stabilities were less than 10%. The extraction recoveries from rat plasma were exceeded 86.0%. The results indicated that there were significant differences between the two groups on pharmacokinetics parameters; the absorptions of four analytes in the depression group were higher than those in the normal group because the liver metabolism and internal environment of the model rats had been affected.

Sex Differences in the Immune System Become Evident in the Perinatal Period in the Four Core Genotypes Mouse.

We have used the four core genotypes (FCG) mouse model, which allows a distinction between effects of gonadal secretions and chromosomal complement, to determine when sex differences in the immune system first appear and what influences their development. Using splenic T cell number as a measure that could be applied to neonates with as yet immature immune responses, we found no differences among the four genotypes at postnatal day 1, but by day 7, clear sex differences were observed. These sex differences were unexpectedly independent of chromosomal complement and similar in degree to gonadectomized FCG adults: both neonatal and gonadectomized adult females (XX and XY) showed 2-fold the number of CD4+ and 7-fold the number of CD8+ T cells versus their male (XX and XY) counterparts. Appearance of this long-lived sex difference between days 1 and 7 suggested a role for the male-specific perinatal surge of testicular testosterone. Interference with the testosterone surge significantly de-masculinized the male CD4+, but not CD8+ splenic profile. Treatment of neonates demonstrated elevated testosterone limited mature cell egress from the thymus, whereas estradiol reduced splenic T cell seeding in females. Neonatal male splenic epithelium/stroma expressed aromatase mRNA, suggesting capacity for splenic conversion of perinatal testosterone into estradiol in males, which, similar to administration of estradiol in females, would result in reduced splenic T cell seeding. These sex steroid effects affected both CD4+ and CD8+ cells and yet interference with the testosterone surge only significantly de-masculinized the splenic content of CD4+ cells. For CD8+ cells, male cells in the thymus were also found to express one third the density of sphingosine-1-phosphate thymic egress receptors per cell compared to female, a male characteristic most likely an indirect result of Sry expression. Interestingly, the data also support a previously unrecognized role for non-gonadal estradiol in the promotion of intra-thymic cell proliferation in neonates of both sexes. Microarray analysis suggested the thymic epithelium/stroma as the source of this hormone. We conclude that some immune sex differences appear long before puberty and more than one mechanism contributes to differential numbers and distribution of T cells.

Daily self-care practices influence exit-site condition in patients having peritoneal dialysis: A multicenter cross-sectional survey.

AIMS: To investigate practice patterns in exit-site care and identify the risk factors for exit-site infection. DESIGN: A quantitative cross-sectional design. METHODS: Data were collected in 12 peritoneal dialysis (PD) centres in 2018. Daily exit-site care practice patterns and exit-site status of patients receiving PD were assessed through interviews and questionnaires. RESULTS/FINDINGS: Most of the 1,204 patients adhered with the protocols about main aspects of exit-site care, such as cleansing agents selection, frequency of cleansing, catheter fixation, and following the catheter protective measures. However, their adherence levels on hand hygiene, mask wearing, observing exit site, examining secretion, and communicating with PD staff were rather low. Eighty-four patients' exit sites were evaluated as problematic exit site (PES). And 186 patients had catheter-related infection (CRI) history. After multivariable logistic regression analysis, diabetes (OR = 1.631), traction bleeding history (OR = 2.697), antibiotic agents use (OR = 2.460), compliance on mask wearing (OR = 0.794), and observing exit site (OR = 0.806) were influencing factors of CRI history. Traction bleeding history (OR = 2.436), CRI history (OR = 10.280), and effective communication (OR = 0.808) with PD staff were influencing factors for PES. CONCLUSIONS: The adherence levels on different aspects of exit-site care were varied in patients having PD. Their self-care behaviours did correlate with the exit-site status. IMPACT: The adherence level of patients' exit-site care practice needs attention of medical staff. Further studies about the optimal procedure in exit-site care were warranted.

Deletion of fibroblast activation protein provides atheroprotection.

AIMS: Fibroblast activation protein (FAP) is upregulated at sites of tissue remodelling including chronic arthritis, solid tumours, and fibrotic hearts. It has also been associated with human coronary atherosclerotic plaques. Yet, the causal role of FAP in atherosclerosis remains unknown. To investigate the cause-effect relationship of endogenous FAP in atherogenesis, we assessed the effects of constitutive Fap deletion on plaque formation in atherosclerosis-prone apolipoprotein E (Apoe) or low-density lipoprotein receptor (Ldlr) knockout mice. METHODS AND RESULTS: Using en face analyses of thoraco-abdominal aortae and aortic sinus cross-sections, we demonstrate that Fap deficiency decreased plaque formation in two atherosclerotic mouse models (-46% in Apoe and -34% in Ldlr knockout mice). As a surrogate of plaque vulnerability fibrous cap thickness was used; it was increased in Fap-deficient mice, whereas Sirius red staining demonstrated that total collagen content remained unchanged. Using polarized light, atherosclerotic lesions from Fap-deficient mice displayed increased FAP targets in terms of enhanced collagen birefringence in plaques and increased pre-COL3A1 expression in aortic lysates. Analyses of the Stockholm Atherosclerosis Gene Expression data revealed that FAP expression was increased in human atherosclerotic compared to non-atherosclerotic arteries. CONCLUSIONS: Our data provide causal evidence that constitutive Fap deletion decreases progression of experimental atherosclerosis and increases features of plaque stability with decreased collagen breakdown. Thus, inhibition of FAP expression or activity may not only represent a promising therapeutic target in atherosclerosis but appears safe at the experimental level for FAP-targeted cancer therapies.