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关键词： Interleukin 17 inhibitor   Secukinumab   Ixekizumab   Brodalumab   Multiple sclerosis   Psoriasis   Psoriatic arthritis   Axial spondyloarthrtitis   SAPHO   Juvenile idiopathic arthritis  

摘要： IL-17 inhibitors may benefit patients with dermatologic or rheumatic diseases and comorbid multiple sclerosis (MS) or MS-like syndrome, either alone or in combination with MS-specific disease-modifying therapies (DMTs). To assess the safety and efficacy of IL-17 inhibitors in patients receiving these treatments for any indication who also suffer from comorbid MS or MS-like syndrome. We systematically reviewed the literature to identify and analyse cases of patients treated with IL-17 inhibitors who also had MS/MS-like syndrome. We analysed 19 studies with an aggregate number of 42 patients (mean age 45 years;58% female). The main primary indications for IL-17 inhibitors were axial spondyloarthritis (axSpA;31%), psoriasis (PsO;26%) and psoriatic arthritis (PsA;24%). Approximately 26% of patients developed MS or MS-like syndrome after exposure to tumour necrosis factor (TNF) inhibitors. Secukinumab (SEC) was the most common IL-17 inhibitor, followed by ixekizumab (IXE), while more than one-third of patients concurrently received MS-specific DMTs. Over a median follow-up of 12.5 months, SEC was discontinued in nine patients as follows: four due to failure to control rheumatic/dermatologic disease, three due to neurological relapse, one due to safety concerns over dual biologic agent use and one due to unknown reasons. Limited evidence suggests that SEC and IXE may be safe and effective treatment options in patients with comorbid MS, either as monotherapies or in combination with MS-specific DMTs.

关键词： Tensile strength  

摘要： Self-healing and stretchable thermoelectric (TE) materials are crucial for the advancement of self-powered flexible wearable devices. Despite recent progress in the field, there remains a gap in developing materials that effectively combine self-healing capabilities with superior thermoelectric performance. In this study, we present a novel water-assisted self-healing, stretchable tetrameric complex ionogel, which integrates polyvinyl alcohol (PVA), cellulose nanofibers (CNF), and polyvinyl pyrrolidone (PVP) to form a dynamic network structure. The innovative approach involves establishing reversible hydrogen bonds within the ionogel and utilizing PVA crystalline segments as nanofillers. We further incorporate the ionic liquid 1-ethyl-3-methylimidazolium dicyanamide salt (EMIM:DCA) into the network, resulting in PVA-CNF-PVP-IL thermoelectric ionogels. The prepared ionogels exhibit remarkable mechanical properties, achieving a tensile strength of 560 kPa and an elongation at break of 587.02%. They also demonstrate impressive thermoelectric characteristics, with an ionic Seebeck coefficient of 8.997 mV K-1 and a conductivity of 36.09 mS cm-1 at 80% relative humidity. Furthermore, the ionogels exhibit excellent elastic tensile and self-healing properties, even after multiple cut/heal and stretch/release cycles, due to abundant noncovalent interactions, including hydrogen bonding and ion-dipole interactions. Importantly, the ionogels hold potential for use in ionic thermoelectric capacitors (ITEC), advancing the development of high-performance, self-healing, and flexible TE devices tailored for wearable applications.

关键词： Severe asthma   biologic   response   real-life   FeNO   anti-IL-5   anti-IL-5R alpha   mepolizumab   benralizumab  

摘要： Objective: It remains unclear whether baseline FeNO levels can predict response to anti-IL5/5R biologic treatment in patients with severe asthma. Methods: We recruited 104 patients with severe eosinophilic asthma treated with anti-IL5/anti-IL5R for at least one year who had measured FeNO values before the beginning of anti-eosinophilic treatment. Population was divided into subjects with FeNO < 25 and >= 25 ppb. In each group we evaluated the changes in pulmonary function (FEV1% and FEF25-75%), clinical (ACT and exacerbations) and steroid-sparing effect, expressed as the modification of daily dosage of inhaled corticosteroids (ICS) and oral corticosteroids (OC), after anti-IL5/anti-IL5R. Results: FEV1 changes after treatment were 3.34 +/- 15,97% in subjects with low baseline FeNO, whereas 11.2 +/- 16.1% in individuals with FeNO >= 25 ppb (p = 0.012). Also, FEF25-75% variations after treatment were different in the two groups: 2.1 +/- 10.7% vs 9.6 +/- 18% in individuals with FeNO < 25 and >= 25 respectively (p = 0.05). Conversely, ACT (4.4 +/- 4.2 vs 5.9 +/- 4.6;p = 0.147), exacerbation changes (-2.46 +/- 1.5 vs -2.9 +/- 1.6;p = 0.137) after treatment were similar in both groups where ICS dosages reduction was alike. On the contrary, the percentage of subjects that reduced/stopped OC treatment after anti-IL5/anti-IL5R was 71.7% in the group with FeNO < 25 ppb whereas 94.1% in individuals with FeNO >= 25 (p = 0.06). Multivariate analysis adjusted for all confounding factors also confirmed the relationship between FeNO >= 25 and improvement in FEV1%/FEF25-75% (beta = 8.372, p = 0.013 and beta = 8.883;p = 0.062 respectively) and the increased probability of discontinuing/reducing OC use (OR:17.838 [95%CI:3.159-100.730];p = 0.001) in the high FeNO group. Conclusion: Pre-biologic FeNO might predict a greater response to treatment with anti-IL-5/5R especially in terms of lung function and OC sparing in subjects with severe eosinophilic/allergic asthma. This could likely be

关键词： Tissue regeneration  

摘要： Inflammatory cells are crucial regulators of infection and regeneration that actively migrate to affected tissues. NF-kB and TNF-alpha (TNF alpha) are master regulators of immune signalling, but their importance for immune cell migration is much less well understood. We have therefore investigated how NF-kB and TNF alpha regulate both macrophage function and behaviour in vivo using a zebrafish model of tissue repair. We show that NF-kB activity differentially regulates TNF alpha activity through Tnf receptors 1a and 1b to control macrophage responses to injury. Loss of NF-kB in macrophages results in elevated TNF alpha expression and results in more directional migration. Impaired NF-kB activity in macrophages perturbs tissue regeneration, causes increased proliferation, altered pro- and anti-inflammatory gene expression and delays fin regeneration. We identify a crucial role for NF-kB modulation of TNF alpha signaling to regulate macrophage responses to tissue injury, which are necessary for effective fin regeneration.

关键词： Mycosis fungoides   s & eacute   zary syndrome   Cutaneous T-cell Lymphoma   IL-4/13 inhibitors   microenvironment  

摘要： IntroductionDupilumab is a monoclonal antibody that inhibits the IL-4 receptor alpha, preventing the binding of IL-4 and IL-13 and the subsequent signal transduction. Mycosis fungoides (MF) and S & eacute;zary syndrome (SS) are the most common form of cutaneous T-cell lymphoma (CTCL). Several cases of MF have been reported following the initiation of dupilumab in patients previously diagnosed with atopic dermatitisAreas coveredThis article is a narrative review of the current state of knowledge regarding the correlation between dupilumab and the development of CTCL. Clinical studies on this topic are reviewed, with a particular focus on the pathogenetic theories proposed to date. Finally, we present a new theory, previously undescribed, regarding the potential role of the cytokine microenvironment in triggering CTCL in patients treated with dupilumabExpert opinionDupilumab could unmask CTCLs by inhibiting IL-4. In fact, a recent study observed that IL-4 plays a key role in maintaining the 'equilibrium phase' between tumor and microenvironment cells. Disruption of this balance could promote the escape of tumor cells and lead to the unmasking of CTCLs.

关键词： Dry eye disease   flow cytometry   inflammation   impression cytology   HLA-DR  

摘要： Purpose: To assess the association of HLA-DR on ocular surface conjunctival cells with the severity of signs and symptoms of dry eye disease (DED) in patients enrolled in the NORTHERN LIGHTS phase 2 trial. Methods: Patients with moderate to severe DED were recruited from 10 different countries in Europe. Symptoms of DED were assessed using the visual analog scale (VAS) global discomfort score, and signs via corneal fluorescein staining (CFS), lissamine green staining, Schirmer's test, and tear osmolarity. HLA-DR expression was evaluated via flow cytometry from impression cytology of conjunctival cells using the EyePrim (TM) device sampled from 205 DED patients. Results: HLA-DR expression was detected in a mean of 3.4% of cells at baseline. HLA-DR expression was significantly associated with corneal staining severity at baseline (p < 0.01). HLA-DR expression was not significantly associated with DED symptoms (VAS global discomfort score), nor lissamine green staining, Schirmer's test, tear osmolarity, or Sjogren's syndrome. Conclusion: HLA-DR was present in a wide range of percentages among DED patients indicating the heterogeneous nature of DED. HLA-DR was significantly associated with corneal fluorescein staining suggesting a correlation of the biomarker with ocular surface damage.

摘要： Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor and frequently has mutations in the transcription factor p53. TAp63 alpha is a member of the p53 protein family that is generally tumor suppressive in various other p53-mutant or p53-deficient cancers. Here, we found that TAp63 alpha inhibited cell proliferation, epithelial-mesenchymal transition (EMT), and migration in several p53-mutant PDAC cell lines. TAp63 alpha transcriptionally repressed IL20RB (which encodes a subunit of the interleukin-20 receptor), potentially by inducing the methylation of its promoter. However, mutations in p53 or KRAS that are common in PDAC increased the abundance of the E3 ligase TRIM21, which promoted the ubiquitin-dependent degradation of TAp63 alpha. Thus, the degradation of TAp63 alpha enabled increases in IL20RB expression and formation of IL-20 receptors, resulting in the activation of downstream JAK1-STAT3 signaling that stimulated the proliferation, EMT, migration, and in vivo metastatic seeding of PDAC cells. Our findings identify a signaling axis involving TRIM21, TAp63 alpha, and IL-20RB in PDAC progression.

关键词： Interferon gamma (IFN-gamma)   tumor necrosis factor alpha (TNF-alpha)   granzyme B   vitiligo   Meta-analysis  

摘要： Background: Vitiligo is a chronic autoimmune skin depigmenting condition. IFN-gamma, TNF-alpha and granzyme B play key roles in vitiligo pathogenesis, some findings suggest their roles may be contradictory. Objective: We aimed to assess IFN-gamma, TNF-alpha and granzyme B levels in blood and skin of vitiligo patients using a meta-analysis approach. Additionally, we evaluated their association with disease activity. Methods: A Meta-analysis was conducted using Review Manager 5.4 software. A total of 55 studies including 3,023 vitiligo patients and 2,534 controls were included in the study. Results: Pooled results from our meta-analysis indicated significantly elevated IFN-gamma protein and transcript levels in blood and skin of vitiligo patients (p < 0.05). TNF-alpha protein levels were also significantly increased in blood and skin of vitiligo patients (p < 0.05). IFN-gamma and TNF-alpha levels were significantly higher in the lesional skin as compared to non-lesional skin (p < 0.05). Furthermore, elevated levels of IFN-gamma and TNF-alpha were observed in patients with active vitiligo (p < 0.05). Additionally, our study suggested a significant increase in granzyme B levels in vitiligo patients (p < 0.05). Conclusion: Overall, the meta-analysis suggests that IFN-gamma, TNF-alpha and granzyme B play a crucial role in vitiligo pathogenesis and progression and may serve as potential therapeutic targets for managing the disease. The PROSPERO registration no. for meta-analysis is CRD42024620274

关键词： antibody   protein engineering   immunology   delivery  

摘要： Interleukin (IL)- 23 is a validated therapeutic target in inflammatory bowel disease. While antibodies targeting IL23 demonstrate clinical efficacy, they face challenges such as high costs, safety risks, and the necessity of parenteral administration. Here, we present a workflow to simultaneously enhance the affinity and protease stability of an anti- IL23R VHH employs both CDR and framework residues to achieve picomolar affinity for IL23R. The engineered VHH remains stable for over 8 h in intestinal fluid and 24 h in fecal samples. Oral administration of this VHH achieves deep pathway inhibition in nonhuman primate blood for over 24 h. With high potency, gut stability, high production yield, and favorable drug- like properties, oral VHHs offer a promising approach for inflammatory bowel diseases.