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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.

关键词： HLA‐DQB1*05:02:01:17 novel allele   Illumina   next‐generation sequencing  

摘要： The HLA-DQB1*05:02:01:17 allele differs from HLA-DQB1*05:02:01:01 by a single nucleotide substitution in intron 3.

关键词： 1型鸭圆环病毒(DuCV)   Cap基因   原核表达   VLPs   多克隆抗体  

摘要： 利用原核表达系统重组表达鸭圆环病毒（DuCV）基因1型Cap蛋白病毒样颗粒（VLPs），纯化后免疫试验兔，检测制备的DuCV-1 Cap VLPs的免疫原性。以DuCV-1型Cap基因为研究对象，应用在线网站对其进行生物信息学分析。对Cap基因序列进行***适应性密码子优化，通过PCR技术扩增不含核定位信号（NLS）的Cap基因，构建重组质粒pET28a-ΔNLS-Cap。IPTG诱导Cap重组蛋白表达，经SDS-PAGE分析及Western blot鉴定，并采用镍柱亲和层析进行纯化。将纯化后的重组蛋白与弗氏佐剂等比例乳化后免疫试验兔，制备多克隆抗体。采用间接ELISA测定抗体效价，采用Western blot检测多克隆抗体特异性。本实验成功构建了重组质粒PET-28a-ΔNLS-Cap，主要以包涵体形式表达，大小约为41.7 kDa。透射电镜观察发现，纯化后的重组蛋白可形成直径约15 nm的病毒样颗粒（VLPs）；间接ELISA法检测重组蛋白兔源多克隆抗体的效价达到1∶160 000以上。Western-blot结果表明，兔抗Cap抗体可以与重组蛋白发生特异性反应。免疫荧光结果显示，兔抗Cap多克隆抗体可以特异性识别由Sf9昆虫细胞表达系统重组表达的DuCV-1Cap蛋白。本试验成功制备了具有免疫原性的DuCV-1Cap VLPs及其兔源多克隆抗体，为进一步研究DuCV亚单位疫苗和相关诊断检测方法奠定了基础。

关键词： 子宫内膜炎   大肠杆菌   布劳恩脂蛋白   脂多糖   奶牛骨髓源巨噬细胞  

摘要： 为了探讨布劳恩脂蛋白(BLP)对大肠杆菌感染诱导奶牛子宫内膜炎中的作用机制，本研究使用LPS、BLP以及LPS联合BLP刺激奶牛骨髓源巨噬细胞(bovine bone marrow-derived macrophages，bBMMs) ；E. coli JE5505、E. coli DH5α感染以及E. coli JE5505感染联合BLP刺激bBMMs。采用ELISA、实时荧光定量PCR和Western-blot等方法检测bBMMs因子分泌、促炎及抗炎信号通路的激活情况，以及TLR2受体的激活对细胞因子分泌的影响。试验结果表明，与E. coli JE5505感染组相比，E. coli DH5α感染组以及E. coli JE5505感染联合BLP刺激组的bBMMs，促炎细胞因子TNF-α和IL-1β的分泌水平显著下降，而抗炎性细胞因子IL-10的分泌水平显著升高。Western-blot分析显示，BLP对bBMMs NF-κB/MAPK通路的激活，以及抗炎信号通路STAT3的表达具有调控作用。在大肠杆菌感染过程中，BLP通过TLR2受体识别，可能依赖于MAPK和NF-κB信号通路的激活，减少了bBMMs促炎因子和趋化因子的产生。此外，BLP还可能通过激活STAT3信号通路增加抗炎因子IL-10的产生，从而有效减轻大肠杆菌感染引起的炎症反应。这表明BLP在调节感染性炎症过程中具有潜在的治疗作用。

关键词： T cell Receptor - TCR   Adoptive cell therapy - ACT   Human leukocyte antigen - HLA   Cervical Cancer  

摘要： Background T-cell receptor (TCR)-T immunotherapy has emerged as a promising strategy for cancer treatment. However, identifying TCRs that can be used to generate TCR-T cells remains challenging due to tumor heterogeneity, the scarcity of tumor-specific T cells, and the diversity of human leukocyte antigens (HLA). To advance TCR-T immunotherapy, it is crucial to develop an efficient and scalable method to identify tumor-specific *** To identify tumor-specific TCRs, epitopes, and their corresponding HLA subtypes, we developed a method for rapidly assembling TCRs identified through the single-cell analysis of T cells from various tumors. For each TCR, only two pairs of oligonucleotides corresponding to the CDR3 regions of TCR-alpha and beta chains needed to be synthesized, enabling the construction of a TCR library quickly in a cost-effective manner. Additionally, we engineered HLA-knockout HEK-293T cells as antigen-presenting cells to express patient-specific HLA-I and neoantigens, and a Jurkat NFAT-GFP reporter cell line for screening antigen-reactive TCRs. The efficacy of our TCR-screening system was validated through a small-scale screening of HPV16-specific TCRs from patients with cervical *** We successfully developed a TCR assembly method that enables the rapid cloning and construction of TCR libraries within 2 days, significantly accelerating the process and reducing costs. Our antigen-presenting system also allows for flexible expression of patient-specific HLA-I molecules, facilitating personalized screening. The Jurkat reporter cells demonstrated high sensitivity for screening functional TCRs. Using published datasets from patients with HPV16-positive cervical cancer, we successfully used our system to isolate a human papillomavirus (HPV)-specific TCR. Through deletion, alanine scanning, and mass spectrometry analysis, we determined that this TCR specifically recognized an 8-mer peptide (MHGDTPTL) from HPV-E7 presented by HLA-B*15:18. Mor

关键词： Cytokine   Immune Checkpoint Inhibitor   Immunotherapy  

摘要： Background Immunocytokines targeting immune checkpoints have shown great potential in overcoming resistance to immune checkpoint blockade (ICB), making them a major focus of development in recent years. However, severe dose-limiting toxicity hindered their clinical application. Therefore, it is vital to develop versatile strategies to improve safety and elucidate the underlying mechanisms of resistance reversal for advancing immunocytokine *** A general prodrug platform was established to construct interleukin (IL)-15 and IL-12-based immunocytokine prodrugs (P-T, P-Y, and P-Y-IL12). The efficacy of the masking strategy was validated by in vitro activity assays and in vivo safety evaluations. Antitumor efficacy of P-T was assessed in two murine cold tumor models. A comprehensive immune correlate analysis was conducted in the tumor and tumor-draining lymph node (TDLN) to identify key effector cells responsible for overcoming resistance, followed by further confirmation with egression of T cell blockade, surgical excision of TDLN, and adoptive transfer experiments. Finally, the synergistic antitumor effects of P-T with other ICB or HPK1 inhibitors were *** P-T or P-Y using steric hindrance from antibody moiety Fab and Fc shields IL-15 activity in circulation, and reactivates it on cleavage by tumor-specific proteases. The universality of this masking strategy is also applicable to IL-12. Compared with prior constructs, P-T and P-Y exhibit prolonged half-life and tumor retention, facilitating sustained intratumoral immune response. P-T demonstrates reduced systemic toxicity but better control of established tumors over the unmasked counterpart. CD44+ CD8+ T cells in TDLNs are identified as critical mediators of P-T's efficacy: blockade of CD44+ CD8+ T cell trafficking into the tumor microenvironment (TME) markedly diminishes its antitumor effects. On P-T treatment, CD44+ CD8+ T cells exhibit enhanced proliferation in TDLNs and improved antit

关键词： Heart disease   TNFR1   TNFR2   Targeted therapy   Personalized precision medicine   Inflammatory cytokines  

摘要： Tumour necrosis factor-alpha (TNF) plays a pivotal role in the inflammatory cascade associated with both cardiovascular pathology and autoimmune conditions. While anti-TNF therapies have shown clinical efficacy in immune-mediated disorders, their use in patients with chronic heart failure (CHF) has produced inconsistent adverse outcomes. This review explores the molecular and cellular mechanisms underlying the inconsistent effects of TNF blockade in heart failure, with a particular focus on receptor-specific signalling, cytokine gene regulation, and intracellular consequences of TNF antagonism. This article highlights the divergent roles of tumor necrosis factor receptor 1 and 2 (TNFR1;TNFR2) in cardiac tissue, highlighting how non-selective TNF neutralisation disrupts the balance between apoptotic and regenerative pathways. Key signalling cascades such as NF-kappa B, p38 MAPK, and PI3K/Akt are discussed in the context of anti-TNF therapy and its effects on myocardial survival, remodelling, and vascular integrity. The review also addresses genetic polymorphisms (e.g. TNF - 308G > A) that may influence therapeutic response and susceptibility to adverse effects. Large-scale clinical trials are needed to assess the long-term safety and effectiveness of receptor-selective TNF modulation. By integrating personalized medicine nanomedicine, biotechnology, and next-generation TNF-targeting strategies could help overcome previous therapeutic failures and lead to more effective treatments for heart disease patients. A deeper understanding of TNF signalling at the molecular level suggests that future therapeutic strategies should prioritise receptor-selective modulation and patient stratification based on genetic and inflammatory biomarkers. Such precision approaches may help overcome the limitations of broad TNF inhibition and enable safer, targeted interventions in CHF.