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Competing Interests: Conflicts of interest Svedbom reports consulting fees from Abbvie, employment and consulting fees from Icon, and lecture fees from Janssen. Ståhle reports consulting, advisory, or lecture fees from Abbvie, Janssen, Novartis, Eli Lilly, Bristol Myers Squibb, and Leo Pharma.

Coastal marine ecosystems are some of the most diverse natural habitats while being highly vulnerable in the face of climate change. The combination of anthropogenic influence from land and ongoing climate change will likely have severe effects on the environment, but the precise response remains uncertain. This study compared an unaffected "control" Baltic Sea bay to a "heated" bay that has undergone artificial warming from cooling water release from a nuclear power plant for ~50 years. This heated the water in a similar degree to IPCC SSP5-8.5 predictions by 2100 as natural systems to study temperature-related climate change effects. Bottom water and surface sediment bacterial communities and their biogeochemical processes were investigated to test how future coastal water warming alters microbial communities; shifts seasonal patterns, such as increased algae blooming; and influences nutrient and energy cycling, including elevated respiration rates. 16S rRNA gene amplicon sequencing and geochemical parameters demonstrated that heated bay bottom water bacterial communities were influenced by increased average temperatures across changing seasons, resulting in an overall Shannon's H diversity loss and shifts in relative abundances. In contrast, Shannon's diversity increased in the heated surface sediments. The results also suggested a trend toward smaller-sized microorganisms within the heated bay bottom waters, with a 30% increased relative abundance of small size picocyanobacteria in the summer (June). Furthermore, bacterial communities in the heated bay surface sediment displayed little seasonal variability but did show potential changes of long-term increased average temperature in the interplay with related effects on bottom waters. Finally, heated bay metabolic gene predictions from the 16S rRNA gene sequences suggested raised anaerobic processes closer to the sediment-water interface. In conclusion, climate change will likely alter microbial seasonality and diversity, leading to prolonged and increased algae blooming and elevated respiration rates within coastal waters., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Seidel, Broman, Ståhle, Nilsson, Turner, Hendrycks, Sachpazidou, Forsman, Hylander and Dopson.)

Increased ocean temperature associated with climate change is especially intensified in coastal areas and its influence on microbial communities and biogeochemical cycling is poorly understood. In this study, we sampled a Baltic Sea bay that has undergone 50 years of warmer temperatures similar to RCP5-8.5 predictions due to cooling water release from a nuclear power plant. The system demonstrated reduced oxygen concentrations, decreased anaerobic electron acceptors, and higher rates of sulfate reduction. Chemical analyses, 16S rRNA gene amplicons, and RNA transcripts all supported sediment anaerobic reactions occurring closer to the sediment-water interface. This resulted in higher microbial diversities and raised sulfate reduction and methanogenesis transcripts, also supporting increased production of toxic sulfide and the greenhouse gas methane closer to the sediment surface, with possible release to oxygen deficient waters. RNA transcripts supported prolonged periods of cyanobacterial bloom that may result in increased climate change related coastal anoxia. Finally, while metatranscriptomics suggested increased energy production in the heated bay, a large number of stress transcripts indicated the communities had not adapted to the increased temperature and had weakened resilience. The results point to a potential feedback loop, whereby increased temperatures may amplify negative effects at the base of coastal biochemical cycling., (© 2022. The Author(s).)

Plaque psoriasis is an immune-mediated inflammatory skin disease associated with the dysregulation of cytokines, especially those involved in the interleukin (IL)-23/IL-17 pathways. In recent years, there has been growing interest in developing biologic therapies that target these pathways. However, inhibition of the cytokines of the IL-23/IL-17 pathways may increase patients' risk of developing fungal infections, particularly oral candidiasis. Therefore, it is important that dermatology practitioners can effectively diagnose and treat oral candidiasis. In this review, we examine the role of the IL-23/IL-17 pathways in antifungal host defense, and provide a practical guide to the diagnosis and treatment of oral candidiasis in patients with psoriasis. Overall, while treatment with anti-IL-17 medications leads to an increased incidence of oral candidiasis in patients with psoriasis, these cases are typically mild or moderate in severity and can be managed with standard antifungal therapy without discontinuing treatment for psoriasis. If applicable, patients with psoriasis should also be advised to practice good oral hygiene and manage or control co-existing diabetes, and should be provided with information on smoking cessation to prevent oral candidiasis., (© 2022. The Author(s).)

Introduction: In the real-world APPRECIATE study (NCT02740218), most patients with psoriasis demonstrated notable improvements on disease severity measures and reported clinically meaningful treatment benefits with apremilast., Objective: We aim to further describe patient-relevant needs and benefits and patient satisfaction with apremilast, including subgroup analyses based on patient characteristics., Methods: APPRECIATE, a multinational, retrospective, cross-sectional study, enrolled patients with chronic plaque psoriasis who started apremilast according to the European label. Patient Benefit Index (PBI; range 0 (no patient-relevant benefit) to 4 (maximum patient-relevant benefit), global PBI score ≥ 1 indicating minimum patient-relevant benefit and ≥ 3 indicating high benefit) and nine-item Treatment Satisfaction Questionnaire for Medication (TSQM-9; range 0-100) were assessed 6 (± 1) months after apremilast initiation and summarized descriptively. Relationships between global PBI and TSQM-9 assessments were analyzed by Pearson correlations., Results: Of 480 enrolled patients, 347 (72.3%) had remained on apremilast at 6 (± 1) months; 90.9% (300/330) achieved global PBI score ≥ 1. Mean (standard deviation) global PBI score was 2.8 (1.2). Higher achievement of global PBI score ≥ 3 was observed in patients with no prior treatments (61.1% (22/36)) or prior phototherapy (64.6% (42/65)) versus prior conventional systemic (54.4% (100/184)) or biologic (38.6% (17/44)) treatment. Strong correlations were observed between the global PBI score and the TSQM-9 global satisfaction and effectiveness subscale scores., Conclusion: Patients continuing apremilast for 6 (± 1) months in APPRECIATE reported patient-relevant treatment benefits. Findings suggest that receiving apremilast earlier versus later in treatment management is consistent with greater improvements in patient-relevant treatment outcomes., (© 2021. The Author(s).)

Positron emission tomography (PET) is a quantitative imaging technique that uses molecules labeled with positron-emitting radionuclides to visualize and measure biochemical processes in the tissues of living subjects. In recent years, different PET tracers have been evaluated for their ability to characterize the atherosclerotic process in order to study the activity of the disease. Here, we describe detailed PET methods for preclinical studies of atherosclerosis and summarize the key methodological aspects of PET imaging in clinical studies of atherosclerosis., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases., Competing Interests: Competing interest statement: N.L., T.H., and O.K. are preparing to file a patent related to the use of transglutaminase 1 autoantibodies as a diagnostic marker., (Copyright © 2021 the Author(s). Published by PNAS.)

The 68 Gallium-labeled 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid conjugated radiolabelled arginine-glycine-aspartic acid peptide ([ 68 Ga]Ga-NODAGA-RGD) is a positron emission tomography (PET) tracer binding to cell surface receptor α v β 3 integrin that is upregulated during angiogenesis and inflammation. We studied whether α v β 3 targeting PET imaging can detect myocardial inflammation in a rat model of autoimmune myocarditis. To induce myocarditis, rats ( n = 8) were immunized with porcine cardiac myosin in complete Freund's adjuvant on days 0 and 7. Control rats ( n = 8) received Freund's adjuvant alone. On day 21, in vivo PET/CT imaging with [ 68 Ga]Ga-NODAGA-RGD followed by ex vivo autoradiography and immunohistochemistry were carried out. Inflammatory lesions were detected histologically in the myocardium of 7 out of 8 immunized rats. In vivo PET images showed higher [ 68 Ga]Ga-NODAGA-RGD accumulation in the myocardium of rats with inflammation than the non-inflamed myocardium of control rats (SUV mean 0.4 ± 0.1 vs. 0.1 ± 0.02; P = 0.00006). Ex vivo autoradiography and histology confirmed that [ 68 Ga]Ga-NODAGA-RGD uptake co-localized with inflammatory lesions containing α v β 3 integrin-positive capillary-like structures. A non-specific [ 68 Ga]Ga-DOTA-(RGE) 2 tracer showed 76% lower uptake than [ 68 Ga]Ga-NODAGA-RGD in the inflamed myocardium. Our results indicate that α v β 3 integrin-targeting [ 68 Ga]Ga-NODAGA-RGD is a potential PET tracer for the specific detection of active inflammatory lesions in autoimmune myocarditis., Competing Interests: AS received consultancy or speaker fees from Amgen, Astra Zeneca, Boehringer Ingelheim, Abbott, and Bayer not related to the present study. JK received consultancy fees from GE Healthcare and AstraZeneca and speaker fees from GE Healthcare, Bayer, and Lundbeck. Boehringer-Ingelheim and Merck, outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jahandideh, Ståhle, Virta, Li, Liljenbäck, Moisio, Knuuti, Roivainen and Saraste.)

Coastal aquatic systems suffer from nutrient enrichment, which results in accelerated eutrophication effects due to increased microbial metabolic rates. Climate change related prolonged warming will likely accelerate existing eutrophication effects, including low oxygen concentrations. However, how the interplay between these environmental changes will alter coastal ecosystems is poorly understood. In this study, we compared 16S rRNA gene amplicon based bacterial communities in coastal sediments of a Baltic Sea basin in November 2013 and 2017 at three sites along a water depth gradient with varying bottom water oxygen histories. The shallow site showed changes of only 1.1% in relative abundance of bacterial populations in 2017 compared to 2013, while the deep oxygen-deficient site showed up to 11% changes in relative abundance including an increase of sulfate-reducing bacteria along with a 36% increase in organic matter content. The data suggested that bacterial communities in shallow sediments were more resilient to seasonal oxygen decline, while bacterial communities in sediments subjected to long-term hypoxia seemed to be sensitive to oxygen changes and were likely to be under hypoxic/anoxic conditions in the future. Our data demonstrate that future climate changes will likely fuel eutrophication related spread of low oxygen zones., (© 2021. The Author(s).)

Objectives: The genetic contribution to psoriatic disease is substantial with a dominating influence of the HLA region. The profile of HLA class I genotypes likely contributes to shaping clinical phenotypes. Herein we aimed to explore such genotypes in cohorts of closely characterised subsets of psoriatic disease with special focus on psoriatic arthritis mutilans (PAM), a severe and rare form of psoriatic arthritis (PsA)., Methods: Cohorts of patients with the diagnosis of psoriasis vulgaris with or without arthritis (n=1217), psoriasis without arthritis (n=534), psoriatic arthritis without mutilating disease (n=337) and psoriatic arthritis mutilans (n=63) were collected and genotyped for HLA class I and II genes, with standardised methodologies. Cases were compared with a healthy control population (n=2468). Case-only and case-control association tests were performed to address the hypothesis of genetic contribution to clinical phenotypes., Results: The presence of HLA-B*27 was strikingly increased in PAM (45%) compared with PsA without mutilating disease (13%) and with healthy controls (13%). However, within the PAM population, HLA-B*27 did not correlate with clinical markers such as number of mutilating joints, radiographic scoring, disease duration and age of disease onset., Conclusions: HLA-B*27 emerges as an important genotype marker for PAM.

Background: Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear., Objective: We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate., Methods: We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies., Results: We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis., Conclusions: Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiovascular effects of glucagon-like peptide-1 receptor (GLP-1R) agonist therapies are potentially mediated by anti-inflammatory effects on atherosclerosis. Our study demonstrates that 68 Ga-NODAGA-exendin-4, a radioligand specifically targeting GLP-1R, detects GLP-1R expression in inflamed atherosclerotic lesions in nondiabetic and diabetic hypercholesterolemic mice. Immunofluorescence staining suggests that GLP-1R is primarily localized in M2 macrophages in lesions. This study describes a new potential tool that may have translational relevance for studies of pharmacological modification of GLP-1R signaling in atherosclerosis.

Importance: Psoriasis is a heterogeneous disease. Improved understanding of prognosis and long-term outcomes in new-onset psoriasis may improve care., Objective: To describe the clinical course of psoriasis and identify possible indicators of long-term outcomes., Design, Setting, and Participants: The Stockholm Psoriasis Cohort was a noninterventional inception cohort study enrolling patients between 2001 and 2005. The present study was conducted from January 15, 2019, to February 5, 2021. At enrollment and 10 years, patients were examined by dermatologists and rheumatologists. Data from examinations were complemented by questionnaires, medical records, and registers. A total of 721 patients with recent-onset psoriasis (<12 months duration), 15 years or older were recruited using advertising and referrals from a broad range of health care settings., Main Outcomes and Measures: Disease severity and psoriatic arthritis (PsA). Recursive partitioning and regression models were implemented to identify probable indicators of long-term outcomes., Results: A total of 721 patients (median [interquartile range] age, 39 [27-55] years; 405 [56%] women), including 542 (75%) with plaque-onset and 174 (24%) with guttate-onset psoriasis, were enrolled. The median follow-up was 9.6 years (interquartile range, 8.8-10.4 years). The cumulative incidence of severe psoriasis at 12 years from enrollment was 21%. Among 509 patients examined clinically after 10 years, 77 of 389 patients (20%) with plaque onset and 56 of 116 (48%) with guttate onset had minimal disease activity without treatment, and 120 of 509 (24%) had PsA. Recursive partitioning identified strata with distinct risks for severe skin disease and PsA: the cumulative incidence of severe disease in patients with plaque phenotype, above-median disease activity, and scalp lesions was 52% (95% CI, 41%-64%), compared with 11% (95% CI, 8%-14%) in patients with below-median disease activity at inclusion; and 48 of 82 patients (59%) with peripheral enthesitis had PsA after 10 years compared with 37 of 304 patients (12%) without initial joint pain (P < .001). Smoking (hazard ratio, 1.70; 95% CI, 1.10-2.63) and activating genes in the interleukin-23 (IL-23) pathway (odds ratio, 1.55; 95% CI, 1.14-2.11) were also significantly associated with a severe disease course. Systemic therapy at or before enrollment was associated with a lower risk for severe disease at 10 years compared with later initiation of systemic therapy (odds ratio, 0.24; 95% CI, 0.06-0.90)., Conclusions and Relevance: The findings of this cohort study suggest that combinations of clinical characteristics at onset and activating genes in the IL-23 pathway are significantly associated with the clinical course of psoriasis, whereas joint pain and peripheral enthesitis may indicate the probability of PsA. Patients within those categories merit specialist referral and closer follow-up. The possibility of modifying the disease course with early systemic intervention should be tested.

Persistent and impaired inflammation impedes tissue healing and is a characteristic of chronic wounds. A better understanding of the mechanisms controlling wound inflammation is needed. In this study, we show that in human wound-edge keratinocytes, the expressions of microRNA (miR)-17, miR-18a, miR-19a, miR-19b, and miR-20a, which all belong to the miR-17∼92 cluster, are upregulated during wound repair. However, their levels are lower in chronic ulcers than in acute wounds at the proliferative phase. Conditional knockout of miR-17∼92 in keratinocytes as well as injection of miR-19a/b and miR-20a antisense inhibitors into wound edges enhanced inflammation and delayed wound closure in mice. In contrast, conditional overexpression of the miR-17∼92 cluster or miR-19b alone in mice keratinocytes accelerated wound closure in vivo. Mechanistically, miR-19a/b and miR-20a decreased TLR3-mediated NF-κB activation by targeting SHCBP1 and SEMA7A, respectively, reducing the production of inflammatory chemokines and cytokines by keratinocytes. Thus, miR-19a/b and miR-20a being crucial regulators of wound inflammation, the lack thereof may contribute to sustained inflammation and impaired healing in chronic wounds. In line with this, we show that a combinatory treatment with miR-19b and miR-20a improved wound healing in a mouse model of type 2 diabetes., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Psoriatic arthritis mutilans (PAM) is the most severe phenotype of psoriatic arthritis due to excessive bone erosion causing joint destruction and decreased functional capacity. The aim of this study was to investigate the prevalence of comorbidities among patients with PAM and the association between comorbidities and joint involvement. Methods: A total of 66 patients aged ≥18 years from the Nordic countries with past or present psoriasis along with at least one mutilated joint were included in the present study. Results: The median number of comorbid conditions per patient was 1 [interquartile range (IQR) 0-2] and 16.7% reported three or more comorbidities. The most frequent comorbidity was hypertension (36.4%). The median number of mutilated joints per patient was 3 (IQR 1-8.3; range 1-38). Conclusion: Two thirds of the patients with PAM reported comorbid conditions and the most frequent was hypertension which affected more than a third of the patients. However, this study was unable to detect any association between comorbidities and the severity of PAM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mistegård, Gudbjornsson, Lindqvist, Laasonen, Ejstrup, Ståhle and Iversen.)

Wound healing is a high energy demanding process that needs a good coordination of the mitochondria with glycolysis in the characteristic highly hypoxic environment. In diabetes, hyperglycemia impairs the adaptive responses to hypoxia with profound negative effects on different cellular compartments of wound healing. miR-210 is a hypoxia-induced microRNA that regulates cellular metabolism and processes important for wound healing. Here, we show that hyperglycemia blunted the hypoxia-dependent induction of miR-210 both in vitro and in human and mouse diabetic wounds. The impaired regulation of miR-210 in diabetic wounds is pathogenic, since local miR-210 administration accelerated wound healing specifically in diabetic but not in non-diabetic mice. miR-210 reconstitution restores the metabolic balance in diabetic wounds by reducing oxygen consumption rate and ROS production and by activating glycolysis with positive consequences on cellular migration. In conclusion, miR-210 accelerates wound healing specifically in diabetes through improvement of the cellular metabolism.

Background: Activation of glucagon-like peptide-1 receptor (GLP-1R) signaling protects against cardiac dysfunction and remodeling after myocardial infarction (MI). The aim of the study was to evaluate 68 Ga-NODAGA-exendin-4 positron emission tomography (PET) for assessment of GLP-1R expression after MI in rats., Methods and Results: Rats were studied at 3 days, 1 and 12 weeks after permanent coronary ligation or a sham-operation. Rats were injected with 68 Ga-NODAGA-exendin-4 and scanned with PET and contrast-enhanced computed tomography (CT) followed by digital autoradiography and histology of left ventricle tissue sections. 68 Ga-NODAGA-exendin-4 PET/CT showed focally increased tracer uptake in the infarcted regions peaking at 3 days and continuing at 1 week after MI. Pre-treatment with an unlabeled exendin-4 peptide significantly reduced 68 Ga-NODAGA-exendin-4 uptake. By autoradiography, 68 Ga-NODAGA-exendin-4 uptake was 8.6-fold higher in the infarcted region and slightly increased also in the remote, non-infarcted myocardium at 1 week and 12 weeks post-MI compared with sham. Uptake of 68 Ga-NODAGA-exendin-4 correlated with the amount of CD68-positive macrophages in the infarcted area and alpha-smooth muscle actin staining in the remote myocardium., Conclusions: 68 Ga-NODAGA-exendin-4 PET detects up-regulation of cardiac GLP-1R expression during healing of MI in rats and may provide information on the activated repair mechanisms after ischemic myocardial injury.

Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum 18 F-labeled 1,4,7-triazacyclononane- N,N',N″ -triacetic acid conjugated folate ( 18 F-FOL) is a PET tracer targeting folate receptor β (FR-β), which is expressed on activated macrophages at sites of inflammation. We evaluated 18 F-FOL PET for the detection of myocardial inflammation in rats with autoimmune myocarditis and studied the expression of FR-β in human cardiac sarcoidosis specimens. Methods: Myocarditis was induced by immunizing rats ( n = 18) with porcine cardiac myosin in complete Freund adjuvant. Control rats ( n = 6) were injected with Freund adjuvant alone. 18 F-FOL was intravenously injected, followed by imaging with a small-animal PET/CT scanner and autoradiography. Contrast-enhanced high-resolution CT or 18 F-FDG PET images were used for coregistration. Rat tissue sections and myocardial autopsy samples from 6 patients with cardiac sarcoidosis were studied for macrophages and FR-β. Results: The myocardium of 10 of 18 immunized rats showed focal macrophage-rich inflammatory lesions, with FR-β expression occurring mainly in M1-polarized macrophages. PET images showed focal myocardial 18 F-FOL uptake colocalizing with inflammatory lesions (SUV mean , 2.1 ± 1.1), whereas uptake in the remote myocardium of immunized rats and controls was low (SUV mean , 0.4 ± 0.2 and 0.4 ± 0.1, respectively; P < 0.01). Ex vivo autoradiography of tissue sections confirmed uptake of 18 F-FOL in myocardial inflammatory lesions. Uptake of 18 F-FOL in inflamed myocardium was efficiently blocked by a nonlabeled FR-β ligand folate glucosamine in vivo. The myocardium of patients with cardiac sarcoidosis showed many FR-β-positive macrophages in inflammatory lesions. Conclusion: In a rat model of autoimmune myocarditis, 18 F-FOL shows specific uptake in inflamed myocardium containing macrophages expressing FR-β, which were also present in human cardiac sarcoid lesions. Imaging of FR-β expression is a potential approach for the detection of active myocardial inflammation., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Aims: Dipeptidyl peptidase 4 (DPP-4) inhibitors have anti-inflammatory and atheroprotective effects. We evaluated the effects of the DPP-4 inhibitor linagliptin on atherosclerotic plaque and hepatic inflammation using histology and 2-deoxy-2-[ 18 F]-fluoro-d-glucose ( 18 F-FDG), a positron emission tomography tracer of inflammation, in a mouse model of hypercholesterolemia and type 2 diabetes., Methods: Igf2/Ldlr -/- Apob 100/100 mice were fed a high-fat diet (HFD) for 8 weeks and then randomly allocated to receive HFD (n = 14), or HFD with added linagliptin (n = 15) for additional 12 weeks. Five mice fed a chow diet were studied as an additional control. At the end of the study, glucose tolerance, aortic and liver uptake of 18 F-FDG, and histology were studied., Results: Mice in linagliptin and HFD groups had similar fasting glucose concentrations, but linagliptin improved glucose tolerance. Aortas of linagliptin and HFD groups showed advanced atherosclerotic plaques with no difference in the mean intima-to-media ratio or number of macrophages in the plaques. Autoradiography showed similar 18 F-FDG uptake by atherosclerotic plaques in linagliptin and HFD groups (plaque-to-wall ratio: 1.7 ± 0.25 vs. 1.6 ± 0.21; p = 0.24). In the liver, linagliptin reduced the histologic inflammation score but had no effect on 18 F-FDG uptake. Compared with chow diet, uptake of 18 F-FDG was similar in the aorta, but higher in the liver after HFD., Conclusions: Linagliptin therapy improved glucose tolerance and reduced hepatic inflammation but had no effect on plaque burden or atherosclerotic inflammation, as determined by histology and 18 F-FDG uptake, in atherosclerotic mice with type 2 diabetes., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Psoriatic arthritis mutilans (PAM) is the most severe phenotype of psoriatic arthritis (PsA)., Purpose: To describe the radiological features in PAM and explore whether existing scoring systems for radiological damage in psoriatic arthritis are applicable for PAM., Material and Methods: Radiographs were scored according to the modified Sharp-van der Heijde (mSvdH) and the Psoriatic Arthritis Ratingen Score (PARS) systems for PsA., Results: At inclusion, 55 PAM patients (49% women, mean age 58 ± 12 years) had conventional radiographs of both hands and feet. A total of 869 PAM joints were detected and 193 joints with ankylosis. The mean total mSvdH score was 213.7 ± 137.8 (41% of maximum) with a higher score for hands than for feet: 136.6 ± 90.1 vs. 79.1 ± 60.9. However, the total score was relatively higher in the feet than in the hands when compared to the highest possible scoring (47% vs. 38% of max). The mean total PARS score was 126.3 ± 79.6 (35% of max). Scoring for joint destruction was higher than for proliferation (22% vs. 11% of max). Strong correlation was found between mSvdH and PARS (r 2  = 0.913). A significant correlation was found between scoring and duration of arthritis and the Health Assessment Questionnaire. History of smoking, BMI, and gender did not influence the scoring values., Conclusions: The two scoring systems studied may not be ideal to indicate progression of PAM in advanced disease since they reach ceiling effects rather early. Therefore, reporting early signs suggestive of PAM, e.g. signs of pencil-in-cup deformities or osteolysis, is crucial. This would reveal the presence of PAM and might lead to improved treatment in order to minimize joint damage., (© The Foundation Acta Radiologica 2020.)

This study showed that treatment with a therapeutic monoclonal immunoglobulin-G1 antibody against phosphorylcholine on oxidized phospholipids preserves coronary flow reserve and attenuates atherosclerotic inflammation as determined by the uptake of 18 F-fluorodeoxyglucose in atherosclerotic mice. The noninvasive imaging techniques represent translational tools to assess the efficacy of phosphorylcholine-targeted therapy on coronary artery function and atherosclerosis in clinical studies., (© 2020 The Authors.)

Venous ulcers are the most common type of human chronic nonhealing wounds and are stalled in a constant and excessive inflammatory state. The molecular mechanisms underlying the chronic wound inflammation remain elusive. Moreover, little is known about the role of regulatory RNAs, such as microRNAs, in the pathogenesis of venous ulcers. We found that both microRNA (miR)-34a and miR-34c were upregulated in the wound-edge epidermal keratinocytes of venous ulcers compared with normal wounds or the skin. In keratinocytes, miR-34a and miR-34c promoted inflammatory chemokine and cytokine production. In wounds of wild-type mice, miR-34a-mimic treatment enhanced inflammation and delayed healing. To further explore how miR-34 functions, LGR4 was identified as a direct target mediating the proinflammatory function of miR-34a and miR-34c. Interestingly, impaired wound closure with enhanced inflammation was also observed in Lgr4 knockout mice. Mechanistically, the miR-34-LGR4 axis regulated GSK-3β-induced p65 serine 468 phosphorylation, changing the activity of the NF-κB signaling pathway. Collectively, the miR-34-LGR4 axis was shown to regulate keratinocyte inflammatory response, the deregulation of which may play a pathological role in venous ulcers., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Alcohol intake affects in great the symptoms and life of  psoriasis patients, although the association of SNPs related to increased alcohol consumption with psoriasis has not been elucidated. Therefore, to investigate the association of psoriasis with established alcohol consumption and dependence-related gene variants we conducted a population-based case-control study including 3743 subjects (776 psoriasis cases and 2967 controls from the general Hungarian population). Genotyping of 23 SNPs at ADH1B, ADH1C, ALDH1A1, ALDH2, SLC6A3, DDC, GABRA2, GABRG1, HTR1B, MAOA, TPH2, CHRM2, GRIN2A, POMC, OPRM1, OPRK1 and BDNF were determined and differences in genotype and allele distributions were investigated. Multiple logistic regression analyses were implemented. Analysis revealed association between C allele of the rs1229984 polymorphism (ADH1B gene) and psoriasis risk (OR additive  = 1.58, 95% CI 1.23-2.03, p < 0.001, OR recessive  = 1.58, 95% CI 1.22-2.04, p = 0.001). Furthermore, the G allele of rs1799971 polymorphism (OPRM1 gene) increased the risk of familial aggregation (OR additive  = 1.99, 95% CI 1.36-2.91, p < 0.001 OR dominant  = 2.01, 95% CI 1.35-3.01, p < 0.001). In subgroups of psoriatic patients with history of early onset and familial aggregation effect allele 'C' of rs1229984 showed association in the additive and recessive models (OR additive  = 2.41, 95% CI 1.26-4.61, p < 0.01, OR recessive  = 2.42, 95% CI 1.26-4.68, p < 0.01). While effect allele 'G' of rs1799971 (OPRM1) also associated with increased risk of early onset and familial aggregation of psoriasis in the additive and dominant models (OR additive  = 1.75, 95% CI 1.27-2.43, p = 0.001, OR dominant  = 1.82, 95% CI 1.26-2.63, p = 0.001). Our results suggest that genetically defined high-risk individuals for alcohol consumption are more common in the psoriasis population.

Chronic wounds represent a major and growing health and economic burden worldwide. A better understanding of molecular mechanisms of normal as well as impaired wound healing is needed to develop effective treatment. Herein we studied the potential role of long noncoding RNA LOC100130476 in skin wound repair. LOC100130476 is an RNA polymerase II-encoded polyadenylated transcript present in both cytoplasm and nucleus. We found that its expression was lower in wound-edge keratinocytes of human chronic wounds compared to normal wounds of healthy donors and intact skin. In cultured keratinocytes, LOC100130476 expression was induced by TGF-β signaling. By reducing LOC100130476 expression with antisense oligos or activating its transcription with CRISPR/Cas9 Synergistic Activation Mediator system, we showed that LOC100130476 restricted the production of inflammatory chemokines by keratinocytes, while enhancing cell migration. In line with this, knockdown of LOC100130476 impaired re-epithelization of human ex vivo wounds. Based on these results, we named LOC100130476 wound and keratinocyte migration-associated long noncoding RNA 2 (WAKMAR2). Moreover, we identified a molecular network that may mediate the biological function of WAKMAR2 in keratinocytes using microarray. In summary, our data suggest that WAKMAR2 is an important regulator of skin wound healing and its deficiency may contribute to the pathogenesis of chronic wounds., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

An increasing number of studies reveal the importance of long noncoding RNAs (lncRNAs) in gene expression control underlying many physiological and pathological processes. However, their role in skin wound healing remains poorly understood. Our study focused on a skin-specific lncRNA, LOC105372576, whose expression was increased during physiological wound healing. In human nonhealing wounds, however, its level was significantly lower compared with normal wounds under reepithelialization. We characterized LOC105372576 as a nuclear-localized, RNAPII-transcribed, and polyadenylated lncRNA. In keratinocytes, its expression was induced by TGF-β signaling. Knockdown of LOC105372576 and activation of its endogenous transcription, respectively, reduced and increased the motility of keratinocytes and reepithelialization of human ex vivo skin wounds. Therefore, LOC105372576 was termed "wound and keratinocyte migration-associated lncRNA 1" (WAKMAR1). Further study revealed that WAKMAR1 regulated a network of protein-coding genes important for cell migration, most of which were under the control of transcription factor E2F1. Mechanistically, WAKMAR1 enhanced E2F1 expression by interfering with E2F1 promoter methylation through the sequestration of DNA methyltransferases. Collectively, we have identified a lncRNA important for keratinocyte migration, whose deficiency may be involved in the pathogenesis of chronic wounds., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

MicroRNAs are short non-coding RNAs that play key roles in regulating biological processes. In this study, we explored effects of chronological and photoageing on the miRNome of human skin. To this end, biopsies were collected from sun-exposed (outer arm, n = 45) and sun-protected (inner arm, n = 45) skin from fair-skinned (phototype II/III) healthy female volunteers of three age groups: young, 18-25 years, middle age, 40-50 years and aged, > 70 years. Strict inclusion criteria were used for photoageing scoring and for chronological ageing. Microarray analysis revealed that chronological ageing had minor effect on the human skin miRNome. In contrast, photoageing had a robust impact on miRNAs, and a set of miRNAs differentially expressed between sun-protected and sun-exposed skin of the young and aged groups was identified. Upregulation of miR-383, miR-145 and miR-34a and downregulation of miR-6879, miR-3648 and miR-663b were confirmed using qRT-PCR in sun-exposed skin compared with sun-protected skin. qRT-PCR analysis revealed that miR-383, miR-34a and miR-134 were differentially expressed in all three age groups both in chronological and photoageing, suggesting a synergetic effect of intrinsic and extrinsic ageing on their expression. In conclusion, our study identifies a unique miRNA signature which may contribute to skin ageing.

Background: Matrix metalloproteinases 2 and 9 (MMP-2/9) play a role in extracellular matrix remodeling after an ischemic myocardial injury. We evaluated 68 Ga-DOTA-peptide targeting MMP-2/9 for the detection of gelatinase expression after myocardial infarction (MI) in rat., Methods: Rats were injected with 43 ± 7.7 MBq of 68 Ga-DOTA-peptide targeting MMP-2/9 at 7 days (n = 7) or 4 weeks (n = 8) after permanent coronary ligation or sham operation (n = 5 at both time points) followed by positron emission tomography (PET). The left ventricle was cut in frozen sections for autoradiography and immunohistochemistry 30 minutes after tracer injection., Results: Immunohistochemical staining showed MMP-2 and MMP-9 expressing cells, CD31-positive endothelial cells, and CD68-positive macrophages in the infarcted myocardium. Autoradiography showed increased tracer uptake in the infarcted area both at 7 days and 4 weeks after MI (MI-to-remote area ratio 2.5 ± 0.46 and 3.1 ± 1.0, respectively). Tracer uptake in damaged tissue correlated with the amount of CD68-positive macrophages at 7 days after MI, and CD31-positive endothelial cells at 7 days and 4 weeks after MI. The tracer was rapidly metabolized, radioactivity in the blood exceeded that of the myocardium, and tracer accumulation in the heart was not detectable by in vivo PET., Conclusions: 68 Ga-DOTA-peptide targeting MMP-2/9 accumulates in the damaged rat myocardium after an ischemic injury, but tracer instability and slow clearance in vivo make it unsuitable for further evaluation.

Background: Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential because they synergize with collagenase for effective pancreatic digestion. The activity of these enzymes is critically dependent on the presence of Ca 2+ ions at a concentration of 5-10 mM. The present study aimed to determine the Ca 2+ concentration during human islet isolation and to ascertain whether the addition of supplementary Ca 2+ is required to maintain an optimal Ca 2+ concentration during the various phases of the islet isolation process., Methods: Human islets were isolated according to standard methods and isolation parameters. Islet quality control and the number of isolations fulfilling standard transplantation criteria were evaluated. Ca 2+ was determined by using standard clinical chemistry routines. Islet isolation was performed with or without addition of supplementary Ca 2+ to reach a Ca 2+ of 5 mM., Results: Ca 2+ concentration was markedly reduced in bicarbonate-based buffers, especially if additional bicarbonate was used to adjust the pH as recommended by the Clinical Islet Transplantation Consortium. A major reduction in Ca 2+ concentration was also observed during pancreatic enzyme perfusion, digestion, and harvest. Additional Ca 2+ supplementation of media used for dissolving the enzymes and during digestion, perfusion, and harvest was necessary in order to obtain the concentration recommended for optimal enzyme activity and efficient liberation of a large number of islets from the human pancreas., Conclusions: Ca 2+ is to a large extent consumed during clinical islet isolation, and in the absence of supplementation, the concentration fell below that recommended for optimal enzyme activity. Ca 2+ supplementation of the media used during human pancreas digestion is necessary to maintain the concentration recommended for optimal enzyme activity. Addition of Ca 2+ to the enzyme blend has been implemented in the standard isolation protocols in the Nordic Network for Clinical Islet Transplantation.

Toll-like receptors (TLR) 2 and 4 are active in sebaceous glands and play a central role in the development of acne. Still, there is only limited knowledge on their effect on sebocytes. In this work we performed global gene expression profile analysis with functional clustering of the differentially regulated genes of TLR1/2 (PAM3CSK4)- and TLR4 (lipopolysaccharide [LPS])-activated SZ95 sebocytes. Both TLR1/2- and 4-activation promoted inflammation in a similar manner already at an early time-point (6 hours), regulating genes involved in inflammation, wound healing and chemotaxis reflecting a more complex cytokine and chemokine regulation than previously known. Importantly, lipid metabolism, the primary feature of sebocytes, was affected at the level of gene expression only at a later time point (24 hours) indicating that sebocytes prioritize to exert a pro-inflammatory phenotype when confronted with a danger signal. Supporting the biological relevance of our results, a meta-analysis revealed that the genes showing the strongest up-regulation were also found up-regulated in acne. Of these genes, serum amyloid A 1/2 (SAA1/2) was confirmed to be a suitable protein marker for in vivo activated sebocytes, underlining their immune-competence, which is structurally defined within sebaceous glands of acne and rosacea skin samples. Altogether our findings demonstrate that sebocytes are not only positioned at the end point of inflammation but are actively involved in shaping the inflammatory response with putative diagnostic and therapeutic relevance., Competing Interests: The authors have declared that no competing interests exist.

Aims: Bariatric surgery is the most effective treatment to tackle morbid obesity and type 2 diabetes, but the mechanisms of action are still unclear. The objective of this study was to investigate the effects of bariatric surgery on intestinal fatty acid (FA) uptake and blood flow., Materials and Methods: We recruited 27 morbidly obese subjects, of whom 10 had type 2 diabetes and 15 were healthy age-matched controls. Intestinal blood flow and fatty acid uptake from circulation were measured during fasting state using positron emission tomography (PET). Obese subjects were re-studied 6 months after bariatric surgery. The mucosal location of intestinal FA retention was verified in insulin resistant mice with autoradiography., Results: Compared to lean subjects, morbidly obese subjects had higher duodenal and jejunal FA uptake (P < .001) but similar intestinal blood flow (NS). Within 6 months after bariatric surgery, obese subjects had lost 24% of their weight and 7/10 diabetic subjects were in remission. Jejunal FA uptake was further increased (P < .03). Conversely, bariatric surgery provoked a decrease in jejunal blood flow (P < .05) while duodenal blood flow was preserved. Animal studies showed that FAs were taken up into enterocytes, for the most part, but were also transferred, in part, into the lumen., Conclusions: In the obese, the small intestine actively takes up FAs from circulation and FA uptake remains higher than in controls post-operatively. Intestinal blood flow was not enhanced before or after bariatric surgery, suggesting that enhanced intestinal FA metabolism is not driven by intestinal perfusion., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Melanoma is one of the deadliest human cancers with limited therapeutic options. MicroRNAs are a class of short noncoding RNAs regulating gene expression at the post-transcriptional level. To identify important miRNAs in melanoma, we compared the miRNome of primary and metastatic melanomas in The Cancer Genome Atlas dataset and found lower miR-203 abundance in metastatic melanoma. Lower level of miR-203 was associated with poor overall survival in metastatic disease. We found that the methylation levels of several CpGs in the MIR203 promoter negatively correlated with miR-203 expression and that treatment with the demethylating agent 5-aza-2-deoxycytidine induced miR-203 expression, which was associated with demethylation of the promoter CpGs, in melanoma cell lines. In vitro, there was a decreased expression of miR-203 in melanoma cell lines in comparison with primary melanocytes. Ectopic overexpression of miR-203 suppressed cell motility, colony formation, and sphere formation as well as the angiogenesis-inducing capacity of melanoma cells. In vivo, miR-203 inhibited xenograft tumor growth and reduced lymph node and lung metastasis. SLUG was shown as a target of miR-203, and knockdown of SLUG recapitulated the effects of miR-203, whereas its restoration was able to reverse the miR-203-mediated suppression of cell motility. These results establish a role for miR-203 as a tumor suppressor in melanoma which suppresses both early and late steps of metastasis. Hence, restoration of miR-203 has therapeutic potential in melanoma., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a ligand of inflammation-inducible vascular adhesion protein-1 (VAP-1). We compared 68 Ga-DOTA- and 18 F-fluorodeoxyribose- (FDR-) labeled Siglec-9 motif peptides for PET imaging of inflammation. Methods . Firstly, we examined 68 Ga-DOTA-Siglec-9 and 18 F-FDR-Siglec-9 in rats with skin/muscle inflammation. We then studied 18 F-FDR-Siglec-9 for the detection of inflamed atherosclerotic plaques in mice and compared it with previous 68 Ga-DOTA-Siglec-9 results. Lastly, we estimated human radiation dosimetry from the rat data. Results . In rats, 68 Ga-DOTA-Siglec-9 (SUV, 0.88 ± 0.087) and 18 F-FDR-Siglec-9 (SUV, 0.77 ± 0.22) showed comparable ( P = 0.29) imaging of inflammation. In atherosclerotic mice, 18 F-FDR-Siglec-9 detected inflamed plaques with a target-to-background ratio (1.6 ± 0.078) similar to previously tested 68 Ga-DOTA-Siglec-9 ( P = 0.35). Human effective dose estimates for 68 Ga-DOTA-Siglec-9 and 18 F-FDR-Siglec-9 were 0.024 and 0.022 mSv/MBq, respectively. Conclusion . Both tracers are suitable for PET imaging of inflammation. The easier production and lower cost of 68 Ga-DOTA-Siglec-9 present advantages over 18 F-FDR-Siglec-9, indicating it as a primary choice for clinical studies.

Chronic wounds represent a major and rising health and economic burden worldwide. There is a continued search toward more effective wound therapy. We found significantly reduced microRNA-132 (miR-132) expression in human diabetic ulcers compared with normal skin wounds and also in skin wounds of leptin receptor-deficient (db/db) diabetic mice compared with wild-type mice. Local replenishment of miR-132 in the wounds of db/db mice accelerated wound closure effectively, which was accompanied by increased proliferation of wound edge keratinocytes and reduced inflammation. The pro-healing effect of miR-132 was further supported by global transcriptome analysis, which showed that several inflammation-related signaling pathways (e.g., NF-κB, NOD-like receptor, toll-like receptor, and tumor necrosis factor signaling pathways) were the top ones regulated by miR-132 in vivo. Moreover, we topically applied liposome-formulated miR-132 mimics mixed with pluronic F-127 gel on human ex vivo skin wounds, which promoted re-epithelialization. Together, our study showed the therapeutic potential of miR-132 in chronic wounds, which warrants further evaluation in controlled clinical trials., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Treatment of psoriasis: before and now  Psoriasis is a multisystem inflammatory disease primarily affecting the skin. Despite its prevalence and considerable effect on quality of life, psoriasis is still underdiagnosed and undertreated. Many patients seek initial evaluation and treatment at primary care level and therefore it is important to know that treatment of psoriasis has advanced tremendously in recent years. Decisions on psoriasis management should be based on assessment of disease severity and phenotype, the existence of physical and psychological comorbidities, the need for referral to dermatologist for specialist care, the patient's preferences and, when possible, identification and elimination of psoriasis trigger factors. Individual treatment goals should be agreed with the patient and treatment should aim to achieve these goals. An individualized, patient centered approach based on the potential of current treatments and a good interpersonal communication between patient and doctor, is essential for effective management of psoriasis.

Purpose: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications, but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein, we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activates the CD40 and 4-1BB pathways, respectively. As many cells in the tumor stroma, including stellate cells and the infiltrating immune cells, express CD40 and some 4-1BB, we hypothesize that LOAd703 activates immunity and simultaneously modulates the biology of the tumor stroma. Experimental Design: Tumor, stellate, endothelial, and immune cells were infected by LOAd703 and investigated by flow cytometry, proteomics, and functional analyses. Results: LOAd703-infected pancreatic cell lines were killed by oncolysis, and the virus was more effective than standard-of-care gemcitabine. In in vivo xenograft models, LOAd703 efficiently reduced established tumors and could be combined with gemcitabine for additional effect. Infected stellate and tumor cells reduced factors that promote tumor growth (Spp-1, Gal-3, HGF, TGFβ and collagen type I), while chemokines were increased. Molecules involved in lymphocyte migration were upregulated on infected endothelial cells. Dendritic cells were robustly stimulated by LOAd703 to produce costimulators, cytokines and chemokines, and such DCs potently expanded both antigen-specific T cells and NK cells. Conclusions: LOAd703 is a potent immune activator that modulates the stroma to support antitumor responses. Clin Cancer Res; 23(19); 5846-57. ©2017 AACR ., (©2017 American Association for Cancer Research.)

MicroRNA (miR)-132 has been identified as a top up-regulated miRNA during skin wound healing and its inhibition impairs wound repair. In a human in vivo surgical wound model, we showed that miR-132 was induced in epidermal as well as in dermal wound-edge compartments during healing. Moreover, in a panel of cells isolated from human skin wounds, miR-132 was found highly expressed in human dermal fibroblasts (HDFs). In HDFs, miR-132 expression was upregulated by TGF-β1. By overexpression or inhibition of miR-132, we showed that miR-132 promoted HDF migration. Mechanistically, global transcriptome analysis revealed that RAS signaling pathway was regulated by miR-132 in HDFs. We found that RAS p21 protein activator 1 (RASA1), a known target of miR-132, was downregulated in HDFs upon miR-132 overexpression. Silencing of RASA1 phenocopied the pro-migratory effect of miR-132. Collectively, our study reveals an important role for miR-132 in HDFs during wound healing and indicates a therapeutic potential of miR-132 in hard-to-heal skin wounds.

Background and Aims: Uptake of the positron emission tomography (PET) tracer 2-deoxy-2-[ 18 F]-fluoro-d- glucose ([ 18 F]FDG) into macrophages is a sensitive marker of inflammation in atherosclerosis. To assess the anti-inflammatory effects of statins, we studied whether atorvastatin therapy reduces aortic [ 18 F]FDG uptake in hypercholesterolemic mice deficient in low-density lipoprotein receptor (Ldlr), and expressing only apolipoprotein B-100 (Ldlr -/- Apob 100/100 )., Methods: Thirty-six Ldlr -/- Apob 100/100 mice were fed a high-fat diet (HFD) for 12 weeks and then allocated to receive a HFD (n = 13), chow diet (Chow, n = 12), or HFD with added atorvastatin (HFD + A, n = 11), for another 12 weeks. In addition to aortic histopathology, [ 18 F]FDG uptake was studied in vivo using PET/computed tomography (CT), and ex vivo by gamma counting of excised aorta., Results: Total cholesterol levels were lower in the Chow and HFD + A groups than in the HFD group (10 ± 3.2, 23 ± 4.9 and 34 ± 9.2 mmol/l, respectively), with the Chow group also showing a lower plaque burden and lower numbers of macrophages in the lesions. Compared to the HFD group, [ 18 F]FDG uptake in the aorta (normalized for blood) was lower in the Chow group in both in vivo (2.1 ± 0.21 vs. 1.7 ± 0.25, p = 0.018) and ex vivo (5.2 ± 2.3 vs. 2.8 ± 0.87, p = 0.011) analyses, whereas atorvastatin had no effect on uptake (2.1 ± 0.42 in vivo and 3.9 ± 1.8 ex vivo). [ 18 F]FDG uptake correlated with plasma total cholesterol levels., Conclusions: Atorvastatin therapy did not show cholesterol-independent effects on inflammation in atherosclerotic lesions in Ldlr -/- Apob 100/100 mice, as determined by histology and [ 18 F]FDG PET, whereas a cholesterol-lowering diet intervention was effective., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Epidermal Langerhans cells (LCs) are spatially separated from dermal dendritic cells (DCs) in healthy human skin. In active psoriasis, maintained by local production of IL-23 and IL-17, inflammatory DCs infiltrate both skin compartments. Here we show that CCR2 + epidermal DCs (eDCs) were confined to lesional psoriasis and phenotypically distinct from dermal DCs. The eDCs exceeded the number of LCs and displayed high expression of genes involved in neutrophil recruitment and the activation of keratinocytes and T cells. Resident LCs responded to toll-like receptor 4 and toll-like receptor 7/8 activation with increased IL-23 production, whereas eDCs additionally produced IL-1β together with IL-23 and tumor necrosis factor. Psoriasis typically recur in fixed skin lesions. eDCs were absent from resolved psoriasis. Instead, LCs from anti-tumor necrosis factor-treated lesions retained high IL23A expression and responded to toll-like receptor stimulation by producing IL-23. Our results reveal phenotypic and functional properties of eDCs and resident LCs in different clinical phases of psoriasis, and the capacity of these cells to amplify the epidermal microenvironment through the secretion of IL-17 polarizing cytokines., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Tissue-resident memory T (Trm) cells form a heterogeneous population that provides localized protection against pathogens. Here, we identify CD49a as a marker that differentiates CD8 + Trm cells on a compartmental and functional basis. In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-γ, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17). In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response. In skin from patients with vitiligo, where melanocytes are eradicated locally, CD8 + CD49a + Trm cells that constitutively expressed perforin and granzyme B accumulated both in the epidermis and dermis. Conversely, CD8 + CD49a - Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease. Overall, CD49a expression delineates CD8 + Trm cell specialization in human epithelial barriers and correlates with the effector cell balance found in distinct inflammatory skin diseases., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)