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In psoriatic arthritis (PsA), predisposing class I HLA alleles, the presence of synovial clonally proliferated CD8 + T cells and autoantibodies all point towards the loss of immune tolerance. However, the key mechanisms that lead to immune dysregulation are not fully understood. In other types of inflammatory arthritis, T regulatory cell (Treg) dysfunction and plasticity at sites of inflammation were suggested to negatively affect peripheral tolerance. We here addressed if Treg variances associate with psoriatic disease. We collected clinical data, sera and peripheral blood mononuclear cells from 13 healthy controls, 21 psoriasis and 21 PsA patients. In addition, we obtained synovial fluid mononuclear cells from 6 PsA patients. We studied characteristics of CD4 + CD25 + CD127loFoxp3 + Tregs by flow cytometry and used ELISA to quantify antibodies against ADAMTSL5, a recently discovered autoantigen in psoriatic disease. In comparison with their circulating counterparts, Tregs from inflamed joints express increased levels of ICOS, CTLA-4 and TIGIT. Furthermore, synovial fluid-derived Tregs have a distinct phenotype, characterized by IL-17A production and upregulation of CD161 and RORγt. We identified a subset of Tregs with intermediate Foxp3 expression as the major cytokine producer. Furthermore, ICOS + Tregs associate with PsA disease activity as measured by PASDAS. Lastly, we observed that presence of the Foxp3int Tregs associates with an increased abundance of anti-ADAMTSL5 autoantibodies. Tregs derived from the inflammatory environment of inflamed PsA joints exhibit a distinct phenotype, which associates with loss of peripheral immune tolerance in psoriatic disease. [ABSTRACT FROM AUTHOR]

Summary: Autoimmune rheumatic diseases (AIRD) are categorized seropositive or seronegative, dependent upon the presence or absence of specific autoreactive antibodies, including rheumatoid factor and anti‐citrullinated protein antibodies. Autoantibody‐based diagnostics have proved helpful in patient care, not only for diagnosis but also for monitoring of disease activity and prediction of therapy responsiveness. Recent work demonstrates that AIRD patients develop autoantibodies beyond those contained in the original categorization. In this study we discuss key mechanisms that underlie autoantibody development in AIRD: defects in early B cell development, genetic variants involved in regulating B cell and T cell tolerance, environmental triggers and antigen modification. We describe how autoantibodies can directly contribute to AIRD pathogenesis through innate and adaptive immune mechanisms, eventually culminating in systemic inflammation and localized tissue damage. We conclude by discussing recent insights that suggest distinct AIRD have incorrectly been denominated seronegative. [ABSTRACT FROM AUTHOR]

Joost J Pouw,1,* Muneer Ahmed,2,* Bauke Anninga,2 Kimberley Schuurman,1 Sarah E Pinder,2 Mieke Van Hemelrijck,3 Quentin A Pankhurst,4,5 Michael Douek,2 Bennie ten Haken1 1MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, the Netherlands; 2Research Oncology, Division of Cancer Studies, King’s College London, Guy’s Hospital, London, UK; 3Cancer Epidemiology Group, Division of Cancer Studies, King’s College London, London, UK; 4Healthcare Biomagnetics Laboratory, University College London, London, UK; 5Institute of Biomedical Engineering, University College London, London, UK *These authors contributed equally to this work Introduction: Breast cancer staging with sentinel lymph node biopsy relies on the use of radioisotopes, which limits the availability of the procedure worldwide. The use of a magnetic nanoparticle tracer and a handheld magnetometer provides a radiation-free alternative, which was recently evaluated in two clinical trials. The hydrodynamic particle size of the used magnetic tracer differs substantially from the radioisotope tracer and could therefore benefit from optimization. The aim of this study was to assess the performance of three different-sized magnetic nanoparticle tracers for sentinel lymph node biopsy within an in vivo porcine model.Materials and methods: Sentinel lymph node biopsy was performed within a validated porcine model using three magnetic nanoparticle tracers, approved for use in humans (ferumoxytol, with hydrodynamic diameter dH =32 nm; Sienna+®, dH =59 nm; and ferumoxide, dH =111 nm), and a handheld magnetometer. Magnetometer counts (transcutaneous and ex vivo), iron quantification (vibrating sample magnetometry), and histopathological assessments were performed on all ex vivo nodes.Results: Transcutaneous “hotspots” were present in 12/12 cases within 30 minutes of injection for the 59 nm tracer, compared to 7/12 for the 32 nm tracer and 8/12 for the 111 nm tracer, at the same time point. Ex vivo magnetometer counts were significantly greater for the 59 nm tracer than for the other tracers. Significantly more nodes per basin were excised for the 32 nm tracer compared to other tracers, indicating poor retention of the 32 nm tracer. Using the 59 nm tracer resulted in a significantly higher iron accumulation compared to the 32 nm tracer.Conclusion: The 59 nm tracer demonstrated rapid lymphatic uptake, retention in the first nodes reached, and accumulation in high concentration, making it the most suitable tracer for intraoperative sentinel lymph node localization. Keywords: superparamagnetic iron oxide, breast cancer, magnetic tracer, ferumoxytol, ferumoxide, Sienna+®

Background: Psoriasis is an immune-mediated inflammatory skin disease. Psoriasis severity evaluation is important for clinicians in the assessment of disease severity and subsequent clinical decision making. However, no objective biomarker is available for accurately evaluating disease severity in psoriasis., Objective: To define and compare biomarkers of disease severity and progression in psoriatic skin., Methods: We performed proteome profiling to study the proteins circulating in the serum from patients with psoriasis, psoriatic arthritis and ankylosing spondylitis, and transcriptome sequencing to investigate the gene expression in skin from the same cohort. We then used machine learning approaches to evaluate different biomarker candidates across several independent cohorts. In order to reveal the cell-type specificity of different biomarkers, we also analyzed a single-cell dataset of skin samples. In-situ staining was applied for the validation of biomarker expression., Results: We identified that the peptidase inhibitor 3 (PI3) was significantly correlated with the corresponding local skin gene expression, and was associated with disease severity. We applied machine learning methods to confirm that PI3 was an effective psoriasis classifier, Finally, we validated PI3 as psoriasis biomarker using in-situ staining and public datasets. Single-cell data and in-situ staining indicated that PI3 was specifically highly expressed in keratinocytes from psoriatic lesions., Conclusion: Our results suggest that PI3 may be a psoriasis-specific biomarker for disease severity and hyper-keratinization., Competing Interests: Declaration of Competing Interest TR, AP and WT is currently an employee of AbbVie, with no conflicts of interest regarding the work of this manuscript. The other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The precise pathogenesis of psoriasis remains incompletely explored. We aimed to better understand the underlying mechanisms of psoriasis, using a systems biology approach based on transcriptomics and microbiome profiling., Methods: We collected the skin tissue biopsies and swabs in both lesional and non-lesional skin of 13 patients with psoriasis, 15 patients with psoriatic arthritis and healthy skin from 12 patients with ankylosing spondylitis. To study the similarities and differences in the molecular profiles between these three conditions, and the associations between the host defence and microbiota composition, we performed high-throughput RNA-sequencing to quantify the gene expression profile in tissues. The metagenomic composition of 16S on local skin sites was quantified by clustering amplicon sequences and counted into operational taxonomic units. We further analysed associations between the transcriptome and microbiome profiling., Results: We found that lesional and non-lesional samples were remarkably different in terms of their transcriptome profiles. The functional annotation of differentially expressed genes showed a major enrichment in neutrophil activation. By using co-expression gene networks, we identified a gene module that was associated with local psoriasis severity at the site of biopsy. From this module, we found a 'core' set of genes that was functionally involved in neutrophil activation, epidermal cell differentiation and response to bacteria. Skin microbiome analysis revealed that the abundances of Enhydrobacter, Micrococcus and Leptotrichia were significantly correlated with the genes in core network., Conclusions: We identified a core gene network that associated with local disease severity and microbiome composition, involved in the inflammation and hyperkeratinization in psoriatic skin., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

The identification of regulatory challenges for nanotechnology-enabled health products, followed by discussions with the involved stakeholders, is the first step towards a strategic planning of how such challenges can be successfully addressed in the future. In order to better understand whether the identified regulatory needs are sector-specific for health products or might also hinder the progress in other domains, the REFINE consortium reached out to communities representing other sectors that also exploit the potential of nanotechnology, i.e. industrial chemicals, food and cosmetics. Through a series of trans-sectorial workshops, REFINE partners identified common as well as sector-specific challenges and discussed possible ways forward. Potential solutions lie in a more strengthen collaboration between regulatory and research communities resulting in a targeted production and exploitation of academic data for the regulatory decision-making. Furthermore, a coordinated use of knowledge sharing platforms and databases, trans-sectorial standardisation activities and harmonisation of regulatory activities between geographical regions are possible ways forward, in line with the upcoming European political initiatives such as the Chemical Strategy for Sustainability (CSS). Finally, we also discuss the perspectives for further development and sustainability of methods and tools developed in the REFINE project., (© 2022. The Author(s).)

Background : Absence of RB1 mutation is rare in retinoblastoma and MYCN amplifications were recently identified in a subset of aggressive retinoblastomas occurring in infants. Here we describe not only the clinical phenotype of MYCN retinoblastoma at presentation, but also the tumor response to the first attempt of conservative management in this context. Methods : Interventional retrospective case report Results : A 6-month-old boy was referred with right leukocoria. Examination under anesthesia revealed a group D unilateral retinoblastoma with an extensive whitish mass and total retinal detachment. Despite partial response following combined sequential intravenous and intra-arterial chemotherapy, tumor relapse in the aqueous humor occurred with posterior chamber involvement over 360°, this transiently controlled by intracameral and intravitreal melphalan injections. Eleven months post-diagnosis the eye was enucleated due to diffuse retinal recurrence invading the ciliary body and obscuring the optic nerve, associated with neovascular glaucoma. Histopathology revealed a poorly differentiated retinoblastoma with diffuse retinal invasion, extending from the superior ciliary body to the inferior equatorial choroid. There was post laminar optic nerve extension without involvement of the surgical margin. RB1 and diffuse MYCN nuclear expression were identified. FISH and SNP-array confirmed MYCN amplification. At 65 months follow-up the patient remained in good health without local recurrence or metastasis. Conclusions : To the best of our knowledge, this study is the first to attempt conservative management of an MYCN retinoblastoma, although secondary enucleation could not be avoided due to highly aggressive recurrence resisting all targeted modalities of chemotherapy.

Objective: To identify novel serum proteins involved in the pathogenesis of PsA as compared with healthy controls, psoriasis (Pso) and AS, and to explore which proteins best correlated to major clinical features of the disease., Methods: A high-throughput serum biomarker platform (Olink) was used to assess the level of 951 unique proteins in serum of patients with PsA (n = 20), Pso (n = 18) and AS (n = 19), as well as healthy controls (HC, n = 20). Pso and PsA were matched for Psoriasis Area and Severity Index (PASI) and other clinical parameters., Results: We found 68 differentially expressed proteins (DEPs) in PsA as compared with HC. Of those DEPs, 48 proteins (71%) were also dysregulated in Pso and/or AS. Strikingly, there were no DEPs when comparing PsA with Pso directly. On the contrary, hierarchical cluster analysis and multidimensional scaling revealed that HC clustered distinctly from all patients, and that PsA and Pso grouped together. The number of swollen joints had the strongest positive correlation to ICAM-1 (r = 0.81, P < 0.001) and CCL18 (0.76, P < 0.001). PASI score was best correlated to PI3 (r = 0.54, P < 0.001) and IL-17 receptor A (r = -0.51, P < 0.01). There were more proteins correlated to PASI score when analysing Pso and PsA patients separately, as compared with analysing Pso and PsA patients pooled together., Conclusion: PsA and Pso patients share a serum proteomic signature, which supports the concept of a single psoriatic spectrum of disease. Future studies should target skin and synovial tissues to uncover differences in local factors driving arthritis development in Pso., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Psoriatic arthritis (PsA) is a heterogeneous, chronic inflammatory musculoskeletal disorder that affects ~0.1% of the population. PsA may severely impact quality-of-life and constitutes a significant economic burden on our health care system. While early effective treatment is deemed essential to prevent irreversible joint damage and functional impairment, not all patients respond to the same disease modifying anti-rheumatic drugs (DMARDs). DMARD options for PsA are rapidly evolving, yet only 50-60% of patients show a satisfactory response to their first-line DMARD therapy. Hence, there is an urgent medical need to predict which patients benefit from a particular treatment. To this end, molecular biomarkers capable of predicting therapeutic response are currently being scrutinized in clinical studies, that together should build a framework for clinical guidelines that improve personalized targeted treatment. In this review new developments within the field of biomarker discovery for predicting therapeutic response to DMARDs in PsA are examined., Competing Interests: Declaration of Competing Interest The authors state no conflict of interest and have no disclosures., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Data-driven gating (DDG) approaches for positron emission tomography (PET) are interesting alternatives to conventional hardware-based gating methods. In DDG, the measured PET data themselves are utilized to calculate a respiratory signal, that is, subsequently used for gating purposes. The success of gating is then highly dependent on the statistical quality of the PET data. In this study, we investigate how this quality determines signal noise and thus motion resolution in clinical PET scans using a center-of-mass-based (COM) DDG approach, specifically with regard to motion management of target structures in future radiotherapy planning applications., Methods: PET list mode datasets acquired in one bed position of 19 different radiotherapy patients undergoing pretreatment [ 18 F]FDG PET/CT or [ 18 F]FDG PET/MRI were included into this retrospective study. All scans were performed over a region with organs (myocardium, kidneys) or tumor lesions of high tracer uptake and under free breathing. Aside from the original list mode data, datasets with progressively decreasing PET statistics were generated. From these, COM DDG signals were derived for subsequent amplitude-based gating of the original list mode file. The apparent respiratory shift d from end-expiration to end-inspiration was determined from the gated images and expressed as a function of signal-to-noise ratio SNR of the determined gating signals. This relation was tested against additional 25 [ 18 F]FDG PET/MRI list mode datasets where high-precision MR navigator-like respiratory signals were available as reference signal for respiratory gating of PET data, and data from a dedicated thorax phantom scan., Results: All original 19 high-quality list mode datasets demonstrated the same behavior in terms of motion resolution when reducing the amount of list mode events for DDG signal generation. Ratios and directions of respiratory shifts between end-respiratory gates and the respective nongated image were constant over all statistic levels. Motion resolution d/d max could be modeled as d/dmax=1-e-1.52(SNR-1)0.52, with d max as the actual respiratory shift. Determining d max from d and SNR in the 25 test datasets and the phantom scan demonstrated no significant differences to the MR navigator-derived shift values and the predefined shift, respectively., Conclusions: The SNR can serve as a general metric to assess the success of COM-based DDG, even in different scanners and patients. The derived formula for motion resolution can be used to estimate the actual motion extent reasonably well in cases of limited PET raw data statistics. This may be of interest for individualized radiotherapy treatment planning procedures of target structures subjected to respiratory motion., (© 2018 American Association of Physicists in Medicine.)

Background: Respiratory syncytial virus (RSV) infection is associated with subsequent wheeze and asthma. We previously reported on the causal relationship between prevention of RSV infection during infancy and reduced frequency of subsequent wheeze using a double-blind, randomised, placebo-controlled trial (MAKI). We continued follow-up and analysed the effect of RSV prevention during infancy on asthma and lung function at age 6 years., Methods: We studied 429 infants born at 32-35 weeks of gestation between 2008-10 who had randomly received either palivizumab for RSV immunoprophylaxis or placebo during the RSV season of their first year of life. After the first year of follow-up, single, assessor-blind follow-up of children continued until they were aged 6 years. Primary outcomes were parent-reported current asthma and forced expiratory volume in 0·5 s (FEV 0·5 ). The trial is registered in the ISRCTN registry, number ISRCTN73641710., Findings: 395 (92%) of 429 participants completed this 6-year follow-up study. Parent-reported current asthma was reported in 28 (14·1%) of 199 children in the RSV prevention group and 47 (24·0%) of 196 children in the placebo group (absolute risk reduction [ARR] 9·9%, 95% CI 2·2 to 17·6). The difference in current asthma, which was a composite endpoint, was due to a difference in infrequent wheeze (one to three episodes in the past year; 12 [6·0%] of 199 vs 26 [13·4%] of 194, ARR 7·4%, 95% CI 1·5 to 13·2). FEV 0·5 percentage predicted values were similar between the RSV prevention group (89·1% [SD 10·6]) and placebo group (90·1% [11·1]), with a mean difference of 1·0 (95% CI -1·3 to 3·3). The proportion of children with current physician-diagnosed asthma was similar between the RSV prevention group (19 [10·3%] of 185) and placebo group (18 [9·9%] of 182), with an ARR of -0·4 (95% CI -6·5 to 5·8)., Interpretation: In otherwise healthy preterm infants, this single-blind, randomised, placebo-controlled trial showed that RSV prevention did not have a major effect on current asthma or lung function at age 6 years. Future research will inform on the effect of RSV prevention on asthma at school age in the general population., Funding: AbbVie., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Bullous lung emphysema is a progressive disease, which may be partly explained by gradual expansion of bullae. These air-spaces arise after destruction of alveolar lung tissue. In some patients, bullae can merge into a giant bulla comprising more than 30% of the hemithorax. This bulla compresses surrounding relatively healthy lung parenchyma and regression results in improvement of pulmonary function, exertional tolerance and quality of life. This can be achieved with medication, surgery and with new experimental bronchoscopic lung volume reduction therapy., Case Description: A 58-year-old man presented at the outpatient clinic because of exertion-induced dyspnoea. Additional diagnostics revealed bullous lung emphysema in which the left lower lobe had been transformed into a single large bulla over the course of 7 years of monitoring. His exertional tolerance continued to decrease gradually until there was an unexpected spectacular improvement of his lung function. This improvement proved to be caused by spontaneous resorption of the bulla., Conclusion: Patients with severe bullous lung emphysema may benefit from resorption of large bullae. This mostly requires treatment, but resorption sometimes can be a spontaneous occurrence.

The standard for the treatment of early non-palpable breast cancers is wide local excision directed by wire-guided localization and sentinel lymph node biopsy (SLNB). This has drawbacks technically and due to reliance upon radioisotopes. We evaluated the use of a magnetic tracer for its localization capabilities and concurrent performance of SLNB using a handheld magnetometer in a porcine model as a novel alternative to the current standard. Ethical approval by the IRCAD Ethics Review Board, Strasbourg (France) was received. A magnetic tracer was injected in varying volumes (0.1-5 mL) subcutaneously into the areolar of the left and right 3rd inguinal mammary glands in 16 mini-pigs. After 4 h magnetometer counts were taken at the injection sites and in the groins. The magnetometer was used to localize any in vivo signal from the draining inguinal lymph nodes. Magnetic SLNB followed by excision of the injection site was performed. The iron content of sentinel lymph nodes (SLNs) were graded and quantified. All excised specimens were weighed and volumes were calculated. Univariate analyses were performed to evaluate correlation. Magnetic SLNB was successful in all mini-pigs. There was a significant correlation (r = 0.86; p < 0.01) between magnetometer counts and iron content of SLNs. Grading of SLNs on both H&E and Perl's staining correlated significantly with the iron content (p = 0.001; p = 0.003) and magnetometer counts (p < 0.001; p = 0.004). The peak counts corresponded to the original magnetic tracer injection sites 4 h after injection in all cases. The mean volume and weight of excised injection site specimens was 2.9 cm(3) (SD 0.81) and 3.1 g (SD 0.85), respectively. Injection of ≥0.5 mL magnetic tracer was associated with significantly greater volume (p = 0.05) and weight of excision specimens (p = 0.01). SLNB and localization can be performed in vivo using a magnetic tracer. This could provide a viable alternative for lesion localization and concurrent SLNB in the treatment of non-palpable breast cancer.

In this study, the relationship between current stress, as perceived by an individual, and dissociative phenomena is explored. All subjects were in an acute and naturally caused stress-situation-sudden threat of dismissal from their jobs in a large multinational corporation. Dissociation and stress were measured at two different times over three months. Since information campaigns and psychological support programs were offered to all participants, levels of stress were expected to decrease significantly. The data show that dissociative experiences are elevated when subjects experience high levels of current stress, though scores fall within the normal non-pathological range. Furthermore, it appears that a decrease in stress level is associated with a significant decrease of dissociative symptoms. The results support a one-directional causal relationship: a decrease in perceived stress leads to a decrease in dissociative phenomena.