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关键词： breast cancer   ferroptosis   HMGB3   IFN-gamma   immunotherapy  

摘要： Our previous studies showed HMGB3 expression may correlate with immunotherapy efficacy in breast cancer patients. Here, we investigated whether HMGB3 overexpression has an impact on anti-PD-1 therapy in triple-negative breast cancer (TNBC) and its molecular mechanisms. Animal models were established to observe the effect of HMGB3 on sensitivity to anti-PD-1 treatment. Correlation of HMGB3 expression and ferroptosis preventive proteins in TNBC patients' tissues with anti-PD-1 therapy efficacy was analyzed. The impact of HMGB3 on IFN-gamma (Interferon-gamma) inhibitory effects and signaling was examined in human TNBC cells where HMGB3 expression was knocked down using siRNA. Moreover, TNBC cells stably transfected with lentiviral vectors containing cDNA of HMGB3 were also used to confirm the effect of overexpression of HMGB3 on IFN-gamma inhibitory effect and signaling. Effect of HMGB3 on IFN-gamma-driven ferroptosis and ferroptosis-associated protein expression were also investigated. Correlation of HMGB3 and IRF1 and GPX4 expression in patient's cancer tissue were also investigated. Our results demonstrated that HMGB3 expression contributes to resistance to anti-PD-1 therapy in vivo. HMGB3 expression correlated with treatment efficacy of immunotherapy and survival in TNBC patients. HMGB3 silence decreased resistance of breast cancer cells to IFN-gamma cytotoxic effect, while HMGB3 overexpression increased resistance of these cancer cells. HMGB3 silence increased STAT1 phosphorylation and IRF1 expression upon IFN-gamma treatment compared with control. Overexpression of HMGB3 inhibited STAT1 phosphorylation and IFN-gamma signaling in TNBC cells. Moreover, HMGB3 also increased STAT3 activation and had an effect of interaction between STAT1 and STAT3. HMGB3 overexpression decreased IFN-gamma-driven ferroptosis in TNBC cells. HMGB3 increased ferroptosis-inhibitory proteins (SLC7A11, GPX4, and SLC3A2) expression in TNBC cells. Ferroptosis inhibition recovers resistance to

关键词： Antigen presentation   Antigen processing   MHC class II   Immunopeptidome  

摘要： Major histocompatibility (MHC) class II molecules can exist in two distinct conformational states based on alternative pairing of transmembrane domain GxxxG dimerization motifs (i.e., M1- and M2-paired MHC class II). M1- and M2-paired MHC class II molecules drive different levels of T cell activation and B cell signaling;consequently, differential peptide loading would impact the level of immune response elicited by various antigens/epitopes. In previous studies of a single model antigen, we show that while peptide from BCR-bound antigen is selectively loaded onto M1-paired I-Ak class II, peptide from fluid phase processing of the same antigen is loaded onto both M1- and M2-paired I-Ak. To expand this analysis, we determined the immunnopeptidomes of M1-paired vs. total I-Ak class II molecules isolated from murine B cells. By comparing the two immunopeptidomes as well as the source proteins (antigens), a picture emerges highlighting the unique access each class II conformer has to antigens from different subcellular compartments. Sequence analysis of the two immunopeptidomes suggests a high degree of similarity between the peptide binding grooves of the two class II conformers. Analysis of class II-associated invariant chain (Ii)-derived peptides reveals the robust presence of a nested set of non-CLIP peptides that associate primarily with M1-paired class II, likely outside of the canonical peptide binding groove. In total, these results further highlight the differential peptide loading of M1- vs. M2paired MHC class II molecules and support the idea that differential peptide loading could impact overall immune responsiveness.

关键词： Seneca Valley virus   LncRNA   IFN-alpha  

摘要： lncRNAs play important regulatory roles in almost every aspect of physiological processes. However, the mechanisms by which animal-encoded lncRNAs regulate the interaction of viral infection with host antiviral immunity are unknown. To explore the mechanisms of lncRNA regulation of SVV infection and interferon responses. We performed complete transcriptome sequencing analysis of porcine kidney 15 (PK-15) after infection with SVV-1 strain and IFN-alpha treatment, and identified and screened the sequencing data to obtain potential functional lncRNA-ISL. selected genes were knocked down using CRISPR/Cas9 guide RNAs (gRNAs), and the results of the sequencing were monitored by qRT-PCR and protein blotting in multiple cell lines for selected gene mRNAs and their proteins as well as SVV infection. The results showed that 68 lncRNAs were significantly altered by IFN-alpha and 176 lncRNAs were significantly altered after SVV infection. We found that lncRNA-ISL gRNA significantly inhibited SVV infection compared to negative gRNA control. The expression of the antiviral ISG G1P3 was significantly increased following lncRNA-ISL gRNA editing compared to negative gRNA control in SVV-infected PK-15 cells. We observed that lncRNA-ISL regulation of SVV was independent of JAK-STAT signaling and not associated with G1P3 DNA methylation. Finally, we confirmed that the regulatory effect of lncRNA-ISL on G1P3 occurs during the initial transcription.

关键词： Nonalcoholic steatohepatitis   Exosomes   Macrophage   TNF antisense oligodeoxynucleotide   2-Deoxy-D-glucose   Sod1  

摘要： Inflammatory mediators tumor necrosis factor (TNF) and interleukin 1 beta (IL1(3), primarily derived from hepatic macrophages in the liver, play a crucial role in the progression of nonalcoholic steatohepatitis (NASH). Meanwhile, intravenously injected exosomes are mainly distributed in the liver and predominantly taken up by hepatic macrophage. Herein, we aimed to evaluate the feasibility of targeted inhibition of TNF and IL1(3 expression in hepatic macrophages via exosomes as a potential therapeutic strategy for NASH. In this study, we demonstrated that antisense oligodeoxynucleotide targeting TNF (ASO-TNF) or 2-deoxy-D-glucose (2DG) effectively suppressed the expression of TNF and/or IL1(3 in macrophages. Exosomes loaded with ASO-TNF or 2DG were able to suppress the expression of TNF and/or IL1(3 in macrophages in vitro or in vivo. Furthermore, infusion of Exo/ASO-TNF or Exo/2DG significantly attenuated experimental steatohepatitis in choline deficient amino acid-defined (CDAA) or methionine and choline deficient (MCD) diet-fed mice. RNA-seq results showed that treatment with Exo/ASO-TNF or Exo/2DG significantly inhibited pro-inflammatory signaling pathways. Mechanistically, we observed that administration of Exo/ASO-TNF or Exo/2DG could attenuate NASH progression by up-regulating the expression of superoxide dismutase 1 (Sod1). Combined, our findings demonstrated that infusion of exosomes loaded with ASO-TNF or 2DG alleviated experimental steatohepatitis in murine models. Thus, infusion of exosomes loaded with anti-inflammatory agents holds promise as a potential therapeutic strategy for NASH treatment.

关键词： HLA-A*11:485   novel allele   sequence-based typing  

摘要： The HLA-A*11:485 allele differs from HLA-A*11:01:01:01 by one nucleotide substitution in codon 39 in exon 2.

关键词： HLA   HLA-DQB1   novel allele   sequencing-based typing  

摘要： The novel allele HLA-DQB1*03:01:59 differs from DQB1*03:01:01:01 by one synonymous nucleotide substitution in exon 2.

关键词： HLA-DQB1*05:03:38   next generation sequencing   novel allele  

摘要： The novel HLA-DQB1*05:03:38 allele was first described in a Chinese individual.

关键词： Breathing training   Mycoplasma pneumonia   Serum inflammatory factors   Characteristics and symptoms   Respiratory function test  

摘要： Objective This study aims to investigate the effects of video scenario-based breathing training on interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in children with Mycoplasma pneumonia. Methods A total of 106 children with Mycoplasma pneumonia treated in our hospital from February 2022 to April 2024 were selected. According to different nursing methods, children receiving routine intervention were assigned to the control group, while those undergoing video scenario-based breathing training were assigned to the training group. The serum inflammatory indexes, improvement time of clinical symptoms and lung function recovery were compared between the two groups before training, and at 1 and 2 weeks after training. Results Before training, there was no statistically significant difference in serum inflammatory and lung function indexes between the two groups (p > 0.05). After 1 and 2 weeks of training, the forced expiratory volume in 1 s (FEV1), peak expiratory flow rate (PEF), and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in both groups increased, with higher values in the training group than in the control group, and the difference was statistically significant (p < 0.05). The time for cough disappearance, wheezing disappearance, lung rales disappearance and high fever abatement in the training group was lower than that in the control group, with statistically significant differences (p < 0.05). The levels of IL-4, IL-6, IL-10, TNF-alpha, and IFN-gamma decreased in both groups, with lower levels in the training group than in the control group, and the difference was statistically significant (p < 0.05). Conclusion Video scenario-based breathing training can improve lung function, alleviate clinical symptoms and signs, and reduce serum inflammatory levels of IL-4, IL-6, IL-10, TNF-alpha and IFN-gamma in children with Mycoplasma pneumonia.

关键词： COVID-19   IL-6   ferritin   C-reactive protein   cytokine storm   immuno-modulation   beta glucans   adjunct treatment  

摘要： BackgroundSeveral biomarkers, including C-reactive protein (CRP), ferritin, D-dimer, and Interleukin-6 (IL-6), are established predictors of disease severity and respiratory failure in patients with *** this randomised clinical study, we evaluated the efficiency of the combination of 2 variants' AFO-202 and N-163 strains of Aureobasidium pullulans produced 1,3-1,6 beta-glucans in comparison with the control arm on these biomarkers in COVID-19 *** RT-PCR positive COVID-19 patients were divided into 2 groups: control (n = 22) and standard treatment;ii. (n = 18) - Standard treatment + combination of AFO-202 and N-163 beta glucans for 15 ***-6 levels significantly decreased in the treatment group on day 7 (P = 0.03) but not by day 15 (P = 0.30). CRP levels in the treatment group decreased at day 7 (5.53 +/- 8.21 mg/L) compared to baseline but showed no significant difference from the control group (4.91 +/- 12.54 mg/L, P = 0.98). At day 15, CRP levels remained lower in the treatment group (5.42 +/- 10.41 mg/L) but increased in the control group (14.0 +/- 37.16 mg/L), with no significant difference (P = 0.52). Ferritin levels dropped significantly in the treatment group by day 15 (from 560.58 +/- 537.30 ng/mL to 127.51 +/- 215.91 ng/mL) but increased in the control (P = 0.98). D-dimer levels decreased in the treatment group by day 15 but were not significantly different from controls (P = 0.56).ConclusionThese results indicate that while co-supplementation with AFO-202 and N-163 beta-glucans led to improvement in CRP, ferritin, and IL-6 levels in COVID-19 patients, only the reduction in IL-6 levels on day 7 reached statistical significance. Further long-term multicentric clinical research is warranted to validate the potential of these supplements as treatment adjuncts, for addressing inflammation in COVID-19, especially in vulnerable populations infected with emerging SARS-CoV-2 variants.