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关键词： osseous sarcoidosis   TNF inhibition   adalimumab   infliximab  

摘要： BackgroundIn this case series, we present longitudinal imaging surveillance of 6 cases of osseous sarcoidosis, each of which was effectively treated with tumor necrosis factor (TNF) *** identified 6 patients from Brooke Army Medical Center with osseous sarcoidosis, who were treated with TNF inhibition and followed with longitudinal imaging studies. Cases of osseous sarcoidosis were defined as having pathologic evidence of noncaseating granulomas on bone biopsy and evidence of osseous lesions on imaging attributable to sarcoidosis by the radiologist, treating clinician, and reviewer. Clinical data were obtained through review of the military electronic medical *** imaging with positron emission tomography/computed tomography, magnetic resonance imaging, and bone scintigraphy assisted in the identification of active disease and clinical remission. Imaging progression of asymptomatic lesions was associated with the eventual development of bone pain 1 to 3 years later. Clinical remission was achieved in all six cases of osseous sarcoidosis and effective doses for TNF inhibition were adalimumab 40 mg subcutaneously every 1 to 2 weeks and infliximab 5 mg/kg every 6 to 8 weeks. Time to complete imaging response ranged from 3 to 8 *** imaging with bone scintigraphy, positron emission tomography/computed tomography, and magnetic resonance imaging demonstrated several benefits including evaluation for occult disease, surveillance of asymptomatic lesions, and evaluation of treatment response. TNF inhibition with adalimumab or infliximab was successful in all cases, and complete resolution of osseous lesions was demonstrated in 5 of 6 patients. Discontinuation of TNF inhibition led to disease recurrence in 2 cases, which prompted the use of long-term immunosuppressive therapy in all treated patients.

关键词： IL-17A   Alveolar epithelial cells   p53   Proteomics   scRNA-seq   Acute lung injury   Pulmonary fibrosis   Curcumin  

摘要： Acute lung injury (ALI) is primarily driven by an intense inflammation in the alveolar epithelium. Key to this is the pro-inflammatory cytokine, Interleukin 17 (IL-17), which influences pulmonary immunity and modifies p53 function. The direct role of IL-17A in p53-fibrinolytic system is still unclear, it is important to evaluate this mechanism to regulate the ALI progression to idiopathic pulmonary fibrosis (IPF). C57BL/6 mice, exposed to recombinant IL-17A protein and treated with curcumin, provided insight into IL-17A mechanisms and curcumin's potential for modulating early pulmonary fibrosis stages. A diverse methodology, including proteomics, single-cell RNA sequencing (scRNA-seq) integration, molecular, and Schroedinger approach were utilized. In silico approaches facilitated the potential interactions between curcumin, IL-17A, and apoptosis-related proteins. A notable surge in the expression levels of IL-17A, p53, and fibrinolytic components such as Plasminogen Activator Inhibitor-1 (PAI-I) was discerned upon the IL17A exposure in mouse lungs. Furthermore, the enrichment of pathways and differential expression of proteins underscored the significance of IL-17A in governing downstream regulatory pathways such as inflammation, NF-kappaB signaling, Mitogen-Activated Protein Kinases (MAPK), p53, oxidative phosphorylation, JAK-STAT, and apoptosis. The integration of scRNA-seq data from 20 IPF and 10 control lung specimens emphasized the importance of IL-17A mediated downstream regulation in PF patients. A potent immuno-pharmacotherapeutic agent, curcumin, demonstrated a substantial capacity to modulate the lung pathology and molecular changes induced by IL-17A in mouse lungs. Human IPF single cell data integration confirmed the effects of IL-17A mediated fibrinolytic components in ALI to IPF progression.

关键词： MMP-13   Osteoarthritis   cytokines   pain   walking exercise  

摘要： Pro-inflammatory cytokines produced by chondrocytes play a crucial role in activating matrix metalloproteinase-13 (MMP-13), leading to an imbalance between the synthesis and degradation of the extracellular matrix (ECM) in osteoarthritis (OA). Although regular walking exercise has been shown to reduce inflammatory cytokine levels in OA animal models, the optimal exercise intensity remains underexplored. Therefore, the aim of this study was to investigate the effects of different intensities of regular walking exercise on the levels of pro-inflammatory cytokines (interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α)), anti-inflammatory cytokine (interleukin-4 (IL-4)), as well as MMP-13 expression in cartilage and pain thresholds in an OA animal model. A total of 30 adult male (6-8 weeks old) were divided into five groups: (1) healthy control; (2) monosodium iodoacetate (MIA)-induce OA model; (3) OA with light-intensity walking (OA1); (4) OA with moderate-intensity walking (OA2); (5) and OA with high- intensity walking (OA3). The exercise intervention began one week after MIA injection and continued for six weeks. Pain threshold, inflammatory cytokine (IL-1, TNF-α, IL-4) levels, and MMP-13 expression were measured using an analgesymeter, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC), respectively. The results demonstrated a significant reduction in IL-1 and TNF-α levels, along with decreased MMP-13 expression and increased IL-4 levels, in all exercise groups (OA1, OA2, OA3) compared to the untreated OA group. Additionally, pain thresholds improved following exercise. However, no significant differences were observed among the three exercise intensities in terms of cytokine levels, MMP-13 expression, or pain threshold. This study highlights that the light-intensity regular walking exercise effectively reduces inflammation, MMP-13 expression, and pain in OA. Further research is needed to elucidate the underlying mechanisms of exercise in

关键词： gamma delta T cells   alpha beta T cells   Acute myeloid leukemia   Cellular immunotherapy   HLA-DR  

摘要： In addition to exhibiting significant cytotoxic capabilities, gamma delta T cells play a crucial role as a bridge between innate and adaptive immunity. Although gamma delta T cells have been demonstrated to orchestrate interactions with other immune cells, their impact on alpha beta T cells in the setting of acute myeloid leukemia (AML) remains unexplored. In this study, we found that functional deficiencies of alpha beta T cells were significantly associated with the downregulation of HLA-DR+ gamma delta T cells in patients newly diagnosed with AML. V delta 2+ T cells, which constitute a predominant subset of gamma delta T cells in human peripheral blood, exhibited elevated levels of HLA-DR following ex vivo expansion. Notably, a lower dose of the expanded V delta 2+ T cells did not induce direct cytotoxicity against AML cells;instead, they significantly enhanced the cytotoxic capacity of primary alpha beta T cells toward AML cells. Furthermore, blockade of HLA-DR on V delta 2+ T cells markedly diminished this facilitating effect. Taken together, our findings demonstrate an important indirect role for V delta 2+ T cells beyond their direct killing ability in the context of anti-AML immunity and provide novel insights into the therapeutic potential of adoptive V delta 2+ T cell therapy.

关键词： Mitochondria   MtDNA   SSc   CGAS   STING   ROS   Oxidative Stress   Centromeres   Cytosolic DNA   IFN-beta   IL-6   Inflammation   Fibrosis  

摘要： Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis, vascular dysfunction, and immune dysregulation. Recent studies have highlighted the crucial role of cellular stress responses and their connection to innate immunity in SSc pathogenesis, particularly the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, which has emerged as a pivotal mediator. In SSc, cGAS detects cytosolic DNA and activates STING, triggering type I interferon production and proinflammatory responses. Errors in chromosome segregation, leading to chromosomal instability (CIN) and micronucleus formation, are major contributors to cytosolic DNA release. Additionally, mitochondrial dysfunction in response to stress signaling leads to the release of mitochondrial DNA (mtDNA) into the cytoplasm, further enhancing cGAS-STING activation, although this mechanism requires further validation. Furthermore, mitochondrial impairment leads to excessive production of reactive oxygen species (ROS), which cleave chromosomal DNA and oxidize mtDNA, contributing to chronic inflammation and fibrosis. Alterations in inflammasome and endosome pathways further amplify interleukin and type I interferon responses. This review highlights the crosstalk between mitochondria, ROS, chromosomal missegregation, and the cGAS-STING pathway in SSc pathogenesis. We also discuss emerging therapeutics targeting the cGAS-STING pathway, which hold promise for regulating disease progression and improving outcomes for SSc patients. Although most evidence remains preclinical and long-term outcome data are scarce, this review underscores the potential of emerging therapeutic strategies and emphasizes the importance of personalized approaches. Further research into the molecular signatures of this pathway in SSc could pave the way for precision medicine strategies in the clinical management of this disease.

关键词： Anal fistula   Jiedu Shengji ointment   Clinical efficacy   IL-6   SAA  

摘要： Objective: Observation of the clinical effect of Jiedu Shengji ointment in treating anal fistula and its impact on serum interleukin-6 and serum amyloid A. Methods: The study is a retrospective cohort study. The clinical comparative study was conducted at Baoding NO.1 Central Hospital, China, between April 2023 to March 2024, and comprised patients diagnosed with anal fistula who underwent surgery. The participants were assigned to control group A and intervention group B according to the treatment method. Control group A was treated with Vaseline gauze dressing, while intervention group B was treated with Jiedu Shengji ointment combined with Vaseline gauze. Treatment outcomes between the groups were compared. Data was analysed using SPSS 20. Results: Of the 60 patients, 30(50%) were in group A;20(66.6%) men and 10(33.3%) women with mean age 32.56 +/- 2.66 years (range: 22-43 years). There were 30(50%) patients in group B;22(73.3%) men and 8(26.7%) women with mean age 32.14 +/- 2.35 years (range: 22-42 years). Total effective rate of treatment in group B was 26 (86.67%) compared to 19 (63.33%) in group A (p<0.05). After 7 and 14 days of treatment, the levels of interleukin-6 and serum amyloid A in group B were significantly better than those in group A (p<0.05). The wound bleeding score, wound healing time, and wound oedema score of group B were significantly better than those of group A (p<0.05). After treatment, the visual analogue scale and the Faecal Incontinence Severity Index scores of group B were significantly better than those of group A (p<0.05). After treatment, the levels of transforming growth factor-(3 and epidermal growth factor in group B were significantly better than those in group A (p<0.05). Conclusion: Jiedu Shengji ointment demonstrated remarkable therapeutic efficacy in patients with surgical treatment for anal fistula.

关键词： SARS-CoV-2   Severe acute respiratory syndrome coronavirus   CAA   Cerebral amyloid angiopathy   LATE-NC   limbic predominant age-related   TDP-43   encephalopathy-neuropathologic changes   AD   Alzheimer’s Disease   IgG   Immunoglobulin G   ANNA-1   type-1 antineuronal nuclear antibody   IFN   Interferon   IL   Interleukin   IL-1RA   Interleukin-1 Receptor Antagonist   IP-10   Interferon gamma-induced protein 10   MCP-1   Monocyte Chemoattractant Protein-1   MIP-1α   Macrophage Inflammatory Protein-1 alpha   TNFα   Tumor Necrosis Factor alpha   VEGF   Vascular Endothelial Growth Factor   RANTES   Regulated upon Activation, Normal T cell Expressed and Secreted  

摘要： Background and Objectives: A spectrum of neurologic complications associated with COVID-19 are well documented. While neuroinflammation in the brain of COVID19 patients likely contributes to these complications, the mechanisms of neuroinflammation and correlates of neurologic complications remain elusive, especially since the etiologic pathogen of COVID-19, SARS-CoV-2, minimally invades the CNS. This study aimed to evaluate markers of neuroinflammation, IgG glycosylation patterns indicative of pro-or anti-inflammatory state, and prevalence of brain auto-reactive antibodies in the CSF of COVID-19 patients and their relationship to brain neuropathology. Methods: We evaluated the CSF of 11 deceased unvaccinated COVID-19 donors and 13 matched non-COVID-19 controls. Markers of neuroinflammation, IgG glycosylation patterns, and brain auto-reactive antibodies were assessed, along with their correlation to brain neuropathology. Statistical analyses were performed to compare groups and assess relationships between variables, using non-parametric tests and bootstrap analysis. Results: COVID-19 CSF showed higher levels of neopterin and ANNA-1, markers of neuroinflammation and autoimmunity, respectively, and lower IFN response compared to non-COVID-19 donors. In brain regions of high microglial activation, IL4 and RANTES were significantly increased. SARS-CoV-2 was undetectable in the CSF and brain of COVID-19 donors, yet anti-SARS-CoV-2 CSF antibodies were detected. Fucosylated IgG were associated with Spike IgG, CSF protein, and soluble CD14, whereas afucosylated bisecting IgG were inversely correlated with Spike IgG. Sialic acid containing IgG were positively correlated with IL1 beta and TNF alpha. These associations were not found in non-COVID-19 donors. Inflammatory agalactosylated fucosylated IgG (G0F) were associated with infiltrating CD4 + T cells in the brains of COVID-19 donors. COVID-19 donor CSF displayed higher levels of auto-reactive antibodies to human brain anti

关键词： antibody mediated rejection   daratumumab   desensitization   pediatric heart transplant   ventricular assist device  

摘要： BackgroundPediatric heart transplant recipients have high rates of alloantibody development and antibody-mediated rejection (AMR). Daratumumab is a novel therapy that targets plasma cells and has been utilized in transplant populations, but data in pediatric populations are limited. Here, we describe the utilization of daratumumab in pediatric heart transplant *** patients at a single institution were treated with daratumumab for AMR (n = 9) or anti-HLA antibody desensitization (n = 3). Three doses of daratumumab were administered with additional doses based on clinical response. For AMR, response to daratumumab was evaluated based on hemodynamics, histopathology, biopsy mRNA expression profiling, ejection fraction, donor-specific antibody titers, and donor-derived cell-free DNA fraction. For desensitization, cPRA pre- and post-daratumumab were ***-five daratumumab infusions were administered to 12 patients (age 0.5-24 years;weight 8-90 kg). Infusion reactions occurred in 12% of infusions;however, none required discontinuation. Nine patients (75%) experienced infection;most were common childhood infections and did not require hospitalization. All 9 AMR patients showed improvement in AMR, and those with chronic AMR benefitted from repeat daratumumab administration. All desensitization patients had dramatic declines in cPRA, and two underwent successful transplantation without rejection 9 months *** report that daratumumab is safe and effective in a small series of pediatric heart transplant patients, including patients as young as 6 months old. Daratumumab could prove to be a valuable tool for desensitization and AMR treatment;however, additional studies are needed to corroborate these findings and determine long-term outcomes.