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摘要： Immunocytokines have emerged as a promising modality in cancer therapy, capitalizing on the precision of antibodies to deliver cytokines selectively to tumours. Yet, the toxicity of the cytokine portion of these antibody-cytokine constructs remains a major dose-limiting issue. We present a new approach to control cytokine function without affecting binding of the targeting moiety. By modifying the cytokine with -cyclooctene carbamates at the lysine positions, we can reduce the binding to the receptor of various highly pro-inflammatory cytokines. Then, using a click-2-release (C2R)-approach, we can reactivate the cytokine activity by reacting it with a variety of tetrazines, through a Diels-Alder-pyridazine-elimination cascade. Finally, we show that the caged cytokines can be conjugated a sortase motif to an unmodified targeting nanobody resulting in a targetable caged immunocytokine construct.

摘要： is the major causative agent of leptospirosis. Humans, canines and livestock animals are susceptible to species and can develop fulminant disease. Rodents serve as reservoir hosts in which the bacteria colonize the renal tubules and are excreted in the urine. The host immune response to spp. remains poorly defined. We show that induces a robust type I interferon (IFN) response in human and murine macrophages that is dependent on the cytosolic dsDNA sensor Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of IFN Genes (STING) signaling pathway. Further, we show that mice deficient in the IFNα/β receptor subunit 1 (IFNAR1) or STING had higher bacterial burdens and increased renal colonization following infection suggesting that cGAS-STING-driven type I IFN is required for the host defense against . These findings demonstrate the significance of cGAS-STING- dependent type I IFN signaling in mammalian innate immune responses to .

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： 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： EPSTI1   dermatomyositis   interferon   myoblasts  

摘要： OBJECTIVES:Epithelial-Stromal Interaction 1 (EPSTI1), an interferon-related gene that has emerged as a gene of notable interest, plays a multifaceted role in cellular function and disease processes. However, the precise role of EPSTI1 in the context of dermatomyositis(DM) remains elusive and requires further exploration. METHODS:To investigate EPSTI1 expression in DM, we analyzed two transcriptome datasets, peripheral blood mononuclear cells (PBMCs) and muscle tissues from our DM cohort. We further validated the findings using RT-qPCR and immunohistochemical staining within our idiopathic inflammatory myopathy (IIM) cohort. Through Small Interfering RNA (siRNA)-mediated knockdown, we delved into the function and underlying mechanisms of EPSTI1 in DM patients. RESULTS:EPSTI1 is significantly upregulated in both PBMCs and muscle tissues of DM patients. A notable positive correlation between EPSTI1 expression and interferon-stimulating genes (ISGs) accompanies this upregulation. Furthermore, EPSTI1 levels were markedly elevated in interferon-β(IFN-β)-stimulated myoblasts. Functional studies have shown that downregulation of EPSTI1 inhibits multiple immune and inflammatory pathways, including antigen processing and presentation, chemokine-mediated signalling, interferon signalling, IL-1-mediated signalling, NIK/NF-κB signalling. EPSTI1 was involved in the expression of HLA-A and the secretion of chemokines in myoblasts mediated by IFN-β. CONCLUSION:EPSTI1 might play an essential role in promoting muscle inflammation in DM by regulating the expression of HLA-A and the secretion of chemokines in myoblasts. Targeting EPSTI1 may represent a novel therapeutic approach for reducing muscle inflammation and damage in DM patients.

关键词： antibody   immunology   oral delivery   protein engineering  

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 inhibitory anti-IL23R VHH for oral use. Cocrystal structure analysis reveals that the 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 a murine colitis model. Furthermore, a single pill provides sustained IL23R 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.

关键词： egg layer chickens   Marek's disease   MHC   genetic resistance  

摘要： Mortality from Marek's disease virus (MDV) infection results in economic loss for the poultry industry. It is controlled by vaccination, but the virus mutates and becomes more virulent. Variation within the MHC is well known to impact the outcomes following MDV infection from research performed utilizing the White Leghorn breed, with laboratory strains of the virus. The effect of the MHC haplotype following MDV challenge was determined from six lines of commercial elite (White Plymouth Rock (two), White Leghorn (three), and Rhode Island Red (one)) egg layer lines, challenged with vv+ virus. Mortality was recorded as sire daughter averages at 16-18 weeks of age from 19 generations of data. Sires were genotyped using a set of MHC-specific SNPs, encompassing 210,000 bp. Across all lines, there was a total of 23 unique MHC haplotypes, of which 15 were found at a frequency greater than 5% and used for further analysis. A significant impact on mortality was found for 16 of the haplotypes, with 9 haplotypes associated with decreased mortality and 7 haplotypes with increased mortality. There were three haplotypes identified in more than one line, allowing cross-line comparisons. The effect of these common haplotypes was consistent (either negative, positive or neutral) between lines.