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关键词： drug survival   elderly   IL-17 inhibitors   IL-23 inhibitors   psoriasis  

摘要： Biologic therapies targeting interleukin (IL)-17 and IL-23 have transformed psoriasis treatment, yet real-world evidence on the impact of age on treatment responses and drug survival is limited. This study aims to compare early (12/16 weeks), mid term (24 weeks) and long term (52 weeks) Psoriasis Area and Severity Index (PASI) responses and drug survival in psoriasis patients aged < 65 versus >= 65 years receiving IL-17 or IL-23 inhibitors. In this retrospective study, 121 patients with moderate-to-severe plaque psoriasis treated with secukinumab, ixekizumab, guselkumab, or risankizumab were analyzed. Patients were stratified into two age groups (< 65, n = 78;>= 65, n = 43). PASI75, PASI90, and PASI < 2 outcomes were assessed at 12/16, 24, and 52 weeks. Drug survival was evaluated via Kaplan-Meier analysis (censoring at 24 months) and Cox regression was used to identify predictors of discontinuation. At 12/16 weeks, the < 65 group achieved significantly higher PASI75 (90.5% vs. 65.1%, p = 0.010), PASI90 (75.7% vs. 32.6%, p = 0.030) and PASI < 2 (55.8% vs. 79.7%, p = 0.006) responses than the >= 65 group. At 52 weeks, PASI75, PASI90, and PASI < 2 rates were similar between groups (86.3% vs. 97.5%, p = 0.055;78% vs. 90%, p = 0.112;85.1% vs. 92.5%, p = 0.253). There were no significant differences between IL-17 and IL-23 inhibitors within any age group. Overall drug survival at 24 months was high (79.6% for < 65 and 90.3% for >= 65, log-rank p = 0.407), with no difference between biologic classes (mean survival: 21.8 vs. 22.4 months, p = 0.520). In Cox regression, female sex (HR 0.23, p = 0.005) and higher baseline PASI (HR 1.093 per point, p = 0.013) predicted discontinuation, whereas age, biologic class, BMI, and prior biologic use were not significant. Despite a delayed initial response, older patients achieve long-term PASI outcomes comparable to younger patients when treated with IL-17 and IL-23 inhibitors. Drug survival is similarly excellent across age groups an

关键词： synovial sarcoma   cell therapy   immunology   disparities  

摘要： Purpose Synovial sarcoma (SS) is aggressive with poor outcomes. Cellular therapies are now FDA-approved for advanced disease, but are restricted to certain HLA-A*02 alleles. We estimate eligibility for cellular therapies by race and *** and Methods Demographic and clinical features of SS cases from 2001 to 2020 were obtained from the United States Cancer Statistics (USCS;NPCR-SEER). Survival analyses were performed overall and by race/ethnicity. The proportion eligible for cellular therapy was estimated by race/ethnicity using previously published data on HLA-A*02 status and MAGE-A4 *** From 2001 to 2020, 10 605 patients (48% female, 64% Non-Hispanic White, 17% Hispanic) with SS were identified. The incidence rate was 1.5-1.8/million/person-years and was stable over time, corresponding to an average of 530 new cases annually. The most common primary site was the extremity (n = 5877;58%), and most patients presented with localized disease (n = 5753;54%). The 5-year cause-specific survival was 60% across all races/ethnicities and 79% for localized, 57% for regional, and 12% for distant disease. Differences by race and ethnicity were found in the proportions of patients expected to be eligible for HLA-restricted cellular therapies targeting MAGE-A4. People of European/European descent had the highest estimated proportion (25%-39%), and people of Asian/Pacific Islander descent had the lowest (11%-17%).Conclusion Engineered T-cells targeting MAGE-A4 have shown encouraging safety and efficacy in advanced SS;however, eligibility restrictions will lead to racial and ethnic disparities. HLA-independent solutions must be developed to counter disparities and ensure all patients have access.

关键词： fracture risk   IL-6 blockade   mortality bias   rheumatoid arthritis   TNF-alpha inhibitors  

关键词： ANCA   glomerulonephritis   IL-7R alpha   T lymphocytes   vasculitis  

摘要： Background and hypothesis Increased T-cell interkeukin (IL)-7R alpha signalling is associated with a poorer prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. These studies examined the functional role of IL-7R alpha (CD127) in experimental glomerulonephritis mediated by anti-myeloperoxidase (MPO) T-cell autoimmunity. We hypothesized that T cells would express IL-7R alpha in the kidney and that blocking the function of IL-7R alpha, without cellular depletion, would be *** Mice were immunized with mouse MPO, then low-dose sheep anti-mouse basement membrane globulin was administered to trigger glomerulonephritis. Flow cytometry and RNA-sequencing characterized intrarenal CD127+-expressing CD4+ and CD8+ T cells in mice with anti-MPO glomerulonephritis. To assess the functional role of IL-7R alpha, mice with established anti-MPO autoimmunity were treated with anti-IL-7R alpha *** Control ovalbumin-immunized mice given anti-basement membrane globulin developed minimal injury, while MPO-immunized mice given anti-basement membrane globulin developed albuminuria with glomerular and tubulointerstitial injury. Numbers of intrarenal IL-7R alpha+ (CD127+) CD4+ and CD8+ T cells were increased in mice with anti-MPO glomerulonephritis. There were 3738 and 2726 genes differentially expressed between intrarenal CD127-PD-1+ and CD127+PD-1- CD8+ and CD4+ T cells, respectively, with substantially overlapping differentially expressed genes between CD8+ and CD4+ T cells. Both CD127-PD-1+ CD8+ and CD4+ T cells were enriched for previously described T-cell exhaustion signatures associated with prognosis in autoimmune disease. As effector memory T cells drive inflammation, we blocked the IL-7R alpha after inducing anti-MPO autoimmunity. Anti-IL-7R alpha antibodies limited histological injury, and reduced albuminuria numbers of glomerular and interstitial leucocytes, with reduced intrarenal chemokine and pro-inflammatory cytokine exp

关键词： crossmatch   deceased donor   disease transmission   flow cytometry   hematological disease   histocompatibility   HLA   living donor   lymphoma   malignancy   organ transplant  

摘要： Unexpected transmission of donor-derived diseases, including infections and malignancies, through organ transplantation are occasionally observed and reported. Subclinical, or otherwise undiagnosed, hematological malignancies in potential donors are rare events and typically not identifiable via standard donor evaluation or laboratory testing. Flow cytometric crossmatching is a specialized assay routinely performed in clinical histocompatibility laboratories for the evaluation of immunological compatibility between recipients and organ donors through the detection of donor-specific antibodies. Here, we report 3 unusual cases of undiagnosed hematological malignancies in the organ donors that were identified during routine pretransplant flow cytometric crossmatching evaluation through abnormalities observed in the lymphocyte staining profile, size, and relative cell events that effectively prevented potential transmission of such donor-derived malignancies to the immunocompromised recipients.

关键词： Acute kidney injury   Inflammation   Oxidative stress   Rats  

摘要： The kidneys have a regulatory role in many diseases with their diuresis function and capacity to maintain electrolyte balance. In case of extensive damage, the kidney's filtration capacity is impaired and cannot fulfill its functions. Fluvoxamine (FLV), an antidepressant agent, has antioxidant and anti-inflammatory effects. This study aimed to investigate the protective effects of FLV against renal tissue damage in the lipopolysaccharide (LPS) induced systemic inflammation model. Thirty-two Wistar Albino rats were divided into four equal groups: control, LPS, LPS + FLV, and FLV alone. Six hours after LPS administration, rats were sacrificed and kidney tissues were removed. Histopathological examination of kidney tissues, immunohistochemical expression of the ACE-1, Cas-9, and interleukin-10 (IL-10), as well as spectrophotometric assessment of total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), urea, creatinine levels, and zonulin-1 (ZO-1), claudin-5 (CL-5), aquaporins 2 and 4 (AQ-2, AQ-4) were evaluated. TOS, OSI, urea, creatinine levels, and Cas-9 expressions were significantly increased, and TAS levels, ACE-1, IL-10, AQ-2, AQ-4, ZO-1, and CL-5 expressions significantly decreased in the LPS group compared with the control group. In addition, marked hyperemia, slight-to-moderate hemorrhages, and degeneration of the tubule epithelial cells were observed in kidney sections in the LPS group, in addition to the inflammatory cell infiltrations. FLV treatment significantly improved all these findings. FLV treatment ameliorates renal tissues against inflammatory scenes and protects renal function by enhancing IL-10 and ACE-1 expressions and preserving AQ-2, AQ-4, CL-5, and ZO-1 expressions.

关键词： Gastrodia elata Blume extract   Sepsis-induced lung injury   IL-23/IL-17 A axis   Neutrophil infiltration  

摘要： The Compendium of Materia Medica recorded that the traditional Chinese medicine Gastrodia elata Blume (G. elata) has applications in antibacterial and antiviral. GE05 was prepared from the rhizome of G. elata and its active ingredients have been proven to alleviate inflammatory response. However, the protective effect and the underlying mechanism of G. elata in sepsis remain unclear. Our study aims to uncover the efficacy and molecular mechanisms of GE05 in ameliorating sepsis-induced lung injury. Here, we have shown that GE05 could inhibit the expression of inflammatory cytokines in peritoneal macrophages. Bioinformatics analysis showed the activation of interleukin (IL)-17 signaling pathway in acute lung injury (ALI) mice. We established septicemia models and showed that GE05 improves survival rates and protects against sepsis-induced lung injury by downregulating the IL-23/IL-17 A axis. Quantitative real- time PCR (qPCR) analysis and immunohistochemistry have indicated that IL-17 A inhibition reduces the release of chemokine ligand (Cxcl) 1, Cxcl2, granulocytemacrophage colony stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF), mitigating neutrophil infiltration-induced lung tissue damage. Meanwhile, GE05 could inhibit the activation of the IL-17 Arelated phosphatidylinositol 3-kinase/ c-Jun N-terminal kinase (PI3K/JNK) signaling pathway, suppressing the expression of tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, and IL-6. These results demonstrated that GE05 is a promising agent that targets the IL-23/IL-17 A axis, providing new way for preventing and treating sepsisinduced lung injury.

关键词： circulating cytokines   inflammageing   physical exercise interventions  

摘要： Background and Objectives:The occurrence of chronic low-grade inflammation during aging, also referred to as "," can impair immunological homeostasis and threaten healthy ageing. Different physical exercise interventions have been proposed to tackle inflammageing. The aim of this umbrella review was to appraise current evidence from systematic reviews, with or without meta-analyses, on the effect of exercise interventions on circulating levels of inflammatory markers C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and the anti-inflammatory marker interleukin 10 (IL-10) in community-dwelling older adults. Research Design and Methods:Thirteen systematic reviews on the effects of long-term exercise on CRP, TNF-α, IL-6, and IL-10 in adults aged 60 years and older were selected from a systematic search in databases PubMed and Web of Science and were included in this umbrella review. Results:Overall, a variety of long-term exercise modalities were able to reduce levels of CRP in older adults. Moreover, most exercise interventions were also able to decrease TNF-α. Some studies showed that long-term exercise can diminish IL-6, but the results are less conclusive. The long-term effects of exercise on IL-10 were less described in the literature, with only two systematic reviews showing increases, decreases, or no effects. Discussion and Implications:Results obtained in this umbrella review show that different exercise modalities can decrease circulating pro-inflammatory parameters CRP, TNF-α, and IL-6 in older adults. More research is needed to appraise the effect of exercise interventions on IL-10 in older adults.

关键词： HLA   HLA-DQA1*03:60   new allele   next-generation sequencing  

摘要： The HLA-DQA1*03:60 allele differs from the HLA-DQA1*03:02:01:01 allele by a single nucleotide at codon 161 in exon 3.