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关键词： ankylosing spondylitis   CREG1   IL33   pathological new bone formation   TREM2(+) macrophages  

摘要： Pathological new bone formation is the main cause of disability in ankylosing spondylitis (AS), and so far, it lacks a targeted therapy. Macrophages are central orchestrators of inflammation progression and tissue remodeling, but their contribution to pathological new bone formation has largely not been explored. Here, it is identified that TREM2(+) macrophages predominated within the sites of new bone formation and adjacent to osteogenic precursor cells. In vivo, both depletion of macrophages and knockout of Trem2 significantly reduced pathological new bone formation in a collagen antibody-induced arthritis (CAIA) model. Specifically, TREM2(+) macrophages promoted osteogenic differentiation of ligament-derived progenitor cells (LDPCs) by secreting CREG1, a secretory glycoprotein involved in cell differentiation and normal physiology. CREG1-IGF2R-PI3K-AKT signaling pathway is involved in TREM2(+) macrophage-mediated pathological new bone formation. In addition, it is found that IL-33 promoted TREM2(+) macrophage differentiation through phosphorylation of STAT6. Targeting the above signalings alleviated new bone formation in the CAIA model. The findings highlight the critical role of IL-33-induced TREM2(+) macrophages in pathological new bone formation and provide potential therapeutic targets for halting spinal ankylosis in AS.

关键词： IL-6   Inflammation   Pig   Rejection   Xenotransplantation  

摘要： The inflammatory cytokine interleukin 6 (IL-6) plays a role in both acute and chronic organ allotransplant rejection. Data suggest that IL-6 inhibition may help prevent or reverse rejection, with large multi-center trials now underway. However, the evidence for the benefit of IL-6 inhibitors in xenotransplantation is limited. IL-6 inhibition has been explored in nonhuman-primate models of xenotransplantation, but no clear consensus exists on its efficacy or the best mode of IL-6 inhibition (anti-IL-6 antibodies, or through IL-6 receptor [IL-6R] blockade). Extra considerations for IL-6 blockade exist in xenotransplantation, as both recipient (human) and xenograftderived (porcine) IL-6 may play roles. The systemic inflammation seen in xenograft recipients (SIXR) contributes to significant morbidity and mortality for the recipient through coagulation dysfunction and augmentation of the immune response. Anti-IL-6 antibodies (e.g., siltuximab) bind to human IL-6 and prevent IL-6R activation, but do not bind to porcine IL-6, and so have no effect in preventing graft-driven inflammatory processes. In contrast, IL6R inhibitors (e.g., tocilizumab) inhibit IL-6 activity by blocking binding of human and porcine IL-6 to human IL6R. Although IL-6R blockade cannot prevent the effect of IL-6 on porcine cells, it probably prevents graft-derived IL-6 from contributing to an inflammatory response in the host. This review outlines the role of IL-6 in xenotransplantation and discusses mechanisms for inhibiting IL-6 to improve recipient survival.

关键词： cosmetic surgery   esthetic surgery   plastic surgery   social media  

摘要： Background: Social media has become a valuable platform for advertising. Instagram is one of the most popular platforms. Many plastic surgeons have utilized this platform to promote themselves and their practices. Having followers on Instagram can provide validity and expand the reach to potential clients. We aim to compare Instagram practices of top 10 plastic surgeon Instagram accounts to those with 10 to 100,000 followers. Methods: Top 10 plastic surgeon Instagram accounts were selected using Google and Instagram search features. Additional plastic surgeon Instagram accounts were selected using Instagram search feature. Each account was evaluated for average number of contents posted daily as well as media type (videos vs photos) of contents posted between November 1, 2022, and February 20, 2023. Statistical analysis was performed using double-tailed unpaired student t test to compare the top 10 account group to the 1000 to 10,000 follower group and 10,000 to 100,000 follower group. Results: When comparing the 1000 to 10,000 follower group and 10,000 to 100,000 follower group to the top 10 plastic surgeon Instagram accounts, there were no significant differences in average number of posts, number of pictures posts, number of video posts, and percentage of video posts. Conclusions: Although this study did not demonstrate a significant difference between Instagram account practices of plastic surgeons with millions of followers to those with 1000 to 100,000, it provides valuable information regarding posting practices of plastics surgeons on Instagram.

关键词： immunopeptidomics   antigen processing and presentation machinery   human leukocyte antigen class I   ACN   acetonitrile   AGC   automatic gain control   APPM   antigen processing and presentation machinery   DDA   data-dependent acquisition   DIA   data-independent acquisition   ER   endoplasmic reticulum   FA   formic acid   FDR   false discovery rate   GO   Gene Ontology   HLA   human leukocyte antigen   HLA-I   human leukocyte antigen class I   IT   injection time   PAKC   panel of APPM KO cell   PLC   peptide loading complex  

摘要： The human leukocyte antigen (HLA) processing and presentation machinery (APPM) is altered in various diseases and in response to drug treatments. Defects in the machinery may change presentation levels or alter the repertoire of presented peptides, globally or in an HLA allele-restricted manner, with direct implications for adaptive immunity. In this study, we investigated the immunopeptidome landscape across a panel of isogenic HAP1 cell line clones, each with a KO of a single gene encoding a key protein in the APPM, including B2M, TAP1, TAP2, TAPBP, IRF2, PDIA3, ERAP1, GANAB, SPPL3, CANX, and CALR. We applied immunopeptidomics and proteomics to assess the successful gene KOs on the protein level, understand how these proteins participate in antigen presentation, and contextualize protein expression and antigen presentation. We validated the absence of the KO proteins in the respective samples and found that knocking-out an APPM component leads to the loss of peptide subsets that are normally presented on the control wildtype cells. We assessed the immunopeptidomes qualitatively and quantitatively, considering factors like peptide diversity, peptide length distribution, and binding affinity to the endogenously expressed HLA alleles in HAP1 cells. We demonstrated prominent HLA allele-restricted alterations in several KO conditions. The absence of CALR, CANX, and TAP1 led to significant changes in HLA allele-specific presentation levels. Overall, this work represents the first systematic analysis of how the absence of individual APPM components, knocked out in a single cell line under controlled conditions, affects the immunopeptidome. This approach could facilitate the creation of predictive tools capable of prioritizing HLA-bound peptides likely to be presented when presentation defects occur, such as in cancer and viral infections.

关键词： MAVS   MASLD   NF kappa beta   TNF   hepatocytes  

摘要： BACKGROUND AND AIMS:Mitochondrial antiviral signaling protein (MAVS) is a critical regulator that activates the host's innate immunity against RNA viruses, and its signaling pathway has been linked to the secretion of proinflammatory cytokines. However, the actions of MAVS on inflammatory pathways during the development of metabolic dysfunction-associated steatotic liver disease (MASLD) have been little studied. APPROACH AND RESULTS:Liver proteomic analysis of mice with genetically manipulated hepatic p63, a transcription factor that induces liver steatosis, revealed MAVS as a target downstream of p63. MAVS was thus further evaluated in liver samples from patients and in animal models with MASLD. Genetic inhibition of MAVS was performed in hepatocyte cell lines, primary hepatocytes, spheroids, and mice. MAVS expression is induced in the liver of both animal models and people with MASLD as compared with those without liver disease. Using genetic knockdown of MAVS in adult mice ameliorates diet-induced MASLD. In vitro, silencing MAVS blunts oleic and palmitic acid-induced lipid content, while its overexpression increases the lipid load in hepatocytes. Inhibiting hepatic MAVS reduces circulating levels of the proinflammatory cytokine TNFα and the hepatic expression of both TNFα and NFκβ. Moreover, the inhibition of ERK abolished the activation of TNFα induced by MAVS. The posttranslational modification O -GlcNAcylation of MAVS is required to activate inflammation and to promote the high lipid content in hepatocytes. CONCLUSIONS:MAVS is involved in the development of steatosis, and its inhibition in previously damaged hepatocytes can ameliorate MASLD.

关键词： kidney transplantation   human leukocyte antigen   complement-dependent cytotoxicity crossmatch   delayed graft function   prognosis  

摘要： Kidney transplantation remains the preferred treatment for patients with end-stage kidney failure. Complement-dependent cytotoxicity (CDC) crossmatch (CDC-XM) and human leukocyte antigen (HLA) typing are two important methods of donor-recipient matching prior to kidney transplantation. The purpose of the present study was to explore the effects of CDC-XM levels and HLA matching on early post-operative clinical outcomes in kidney transplant recipients. A total of 112 consecutive recipients who underwent allogeneic kidney transplantation were selected and their data collected, including pre-operative general information, indicators associated with renal function, red blood cell and white blood cell counts, the blood glucose level at each follow-up time point and both the incidence of adverse events following transplantation and their risk factors. During the follow-up period, statistical methods were used to compare and systematically analyze the differences in clinical indicators and adverse events between each groups. In each different groups that were assigned for the CDC-XM levels and HLA matching, the differences in the clinical indicators between the groups during the follow-up period were mainly centered on the first week post-transplantation, with the greatest differences being identified for the renal function-associated indicators, whereas the observed recovery was essentially comparable between 1-6 months. According to the multivariate analysis, recipients of age >= 40 years and with a BMI >= 25 tended to have an increased risk of delayed graft function (DGF), whereas the risk was reduced when the organ had been donated by a living donor and also when the number of HLA mismatches was 0-2. In conclusion, the present study showed that CDC-negativity and improved HLA matching help to promote the recovery of renal function in kidney transplant recipients during the early post-operative period. Patients who met the conditions of CDC-negativity and fewer HLA mism

关键词： pediatric   loss of response   drug persistence   genotype  

摘要： INTRODUCTION: Human leukocyte antigen (HLA) DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF alpha) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. METHODS: We analyzed banked serum from patients with CD aged <21 years enrolled in clinical outcomes of Methotrexate Binary Therapy in practice, a multicenter, prospective randomized trial of anti-TNF alpha monotherapy vs combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. RESULTS: A trend toward increased treatment failure among HLA DQA1*05-positive participants was not significant (hazard ratio 1.58, 95% confidence interval [CI] 0.95-2.62;P = 0.08). After stratification by HLA DQA1*05 and by methotrexate vs placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05-positive patients on placebo (hazard ratio 0.31, 95% CI 0.13-0.70;P = 0.005). A trend toward increased ADA development among HLA DQA1*05-positive participants was not significant (odds ratio 1.96, 95% CI 0.90-4.31, P = 0.09). After further stratification, HLA DQA1*05-negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05-positive patients on placebo (odds ratio 0.12, 95% CI 0.03-0.55;P = 0.008). DISCUSSION: In a randomized trial of children with CD initiating anti-TNF alpha, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

关键词： Parkia pendula polysaccharides   Acute toxicity   Gastroprotective effect  

摘要： We investigated the safety of Parkia pendula exudate polysaccharide (PePp) for acute toxicity and its gastroprotective effect on ethanol-induced gastric ulcers. In the acute toxicity test, animals were treated with a single dose of PePp (2000 mg/kg body weight) and evaluated for behavioral parameters, morbidity and mortality;also biochemical, hematological, and histopathological analysis. The mice were pretreated with a single dose of PePp (10, 25, 50 mg/kg) or ranitidine (80 mg/kg) before gastric ulcer induction with ethanol (99.9 %, orally). Subsequently, the stomachs were analyzed for macroscopic and histopathological parameters and the activity of catalase (CAT), superoxide dismutase (SOD), lipid peroxidation, and cytokines IL-6, TNF-alpha and IL-10. PePp did not cause any changes in acute toxicity parameters. Pretreatment with PePp inhibited the formation of gastric ulcers by 52 %, 71 %, and 83 % at doses of 10, 25 and 50 mg/kg, respectively. Macroscopic improvements and treating gastric tissue exudative inflammatory infiltrate reduction were dose-dependent on PePp. In gastric tissue, PePp presented antioxidative effects, evidenced by increasing CAT and SOD activities and reducing lipid peroxidation;it also showed anti-inflammatory effects, evidenced by reduced IL-6 and TNF-alpha levels and elevated IL-10 levels. PePp is toxicologically safe and has a gastroprotective effect on ethanol-induced gastric ulcers.

关键词： dupilumab   epidermal differentiation   ichthyosis   IL-4/IL-13 blockade   Netherton syndrome  

摘要： Netherton syndrome (NS) is a rare ichthyosis caused by SPINK5-null mutations, resulting in erythroderma, ichthyosis linearis circumflexa, and atopic diathesis. Elevated serum IgE levels and activation of the KLK5-PAR2-TSLP axis suggest involvement of Th2-skewed immunity in NS. In this pilot study, we investigated the effects of IL-4/IL-13 blocking with dupilumab on NS features. At baseline, Th2-chemokines CCL11, CCL17, CCL18, CCL26, and serum IgE were more elevated in atopic dermatitis (AD) than in NS vs. controls (ctrls). AD exhibited elevated serum levels of CCL27, LDH, and eosinophils, while NS showed higher levels of IL-9 and IL-18. Epidermal aberrations, including acanthosis and SC-detachment, were present in NS versus ctrls. The number of CD3+ T cells increased, while CD1a + Langerhans cell numbers decreased in NS skin. Amounts of KLK5 were reduced, and the distribution of KLK7 was abnormal in NS epidermis as compared to ctrls. Reduced amounts of FLG, CDSN, and DSG1 highlight impaired keratinocyte late differentiation in NS. Amounts of epidermal TSLP were diminished. Upon dupilumab treatment, clinical improvement in NS began as early as week 8 and continued up to 30 months, with no serious side effects reported. Serum levels of IgE, CCL17, CCL26, IFN-gamma and IL-18 decreased upon IL-4/IL-13 blockade, and alterations of cutaneous immune cells improved in NS. Furthermore, the epidermal protease inhibitor WFDC12 expression increased after dupilumab treatment, concurring with improved and partially normalised epidermal structure, including increased FLG, CDSN, and DSG1. These data highlight Th2-skewed immunity in NS and emphasise the amelioration of NS features through dupilumab treatment.