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关键词： Cortisol   Interleukins   Pregnancy   Perceived stress   Depressive symptoms  

摘要： Background: Individuals undergo significant stress throughout pregnancy and are at high risk for depressive symptoms. Elevated stress and depressive symptoms are associated with inflammatory processes and adverse maternal-infant outcomes. However, the biological processes associated with psychosocial outcomes and the maternal immune system remain unclear. As such, we aimed to examine associations among perceived stress, depressive symptoms, salivary IL-1 beta, IL-6, and CRP levels, and hair and salivary cortisol levels during the second and third trimesters of pregnancy. Methods: We conducted an ancillary study consisting of 37 pregnant individuals. Participants collected salivary samples and measures of perceived stress and depression at 17-19 weeks, 25-27 weeks, and 32-34 weeks gestation. We collected a one-time hair sample between 36 and 40 weeks. Provided salivary samples were used to detect changes in cortisol, IL-1 beta, IL-6, and CRP levels. Hair was used to detect changes in cortisol levels throughout pregnancy. Results: Elevated levels of perceived stress and depressive symptoms are associated with increased salivary CRP levels, respectively (p = 0.0142, p = 0.0008). Salivary and hair cortisol increased significantly throughout the second and third trimesters of pregnancy (p = 0.0004 and p < 0.0001). We also observed variations in IL-6 during pregnancy (p = 0.029) and significant increases between 25 and 27 weeks (p = 0.016). Conclusion: Salivary samples may provide a non-invasive measurement of alterations in cytokine and cortisol levels in pregnant individuals reporting elevated stress and depressive symptoms. These may be candidate biomarkers for mechanistic study possibly aiding providers in early detection of deleterious immunological processes which could result in adverse maternal-infant outcomes.

关键词： IFN-gamma   Prognosis   scRNA-seq   Immunogenicity   Proliferation  

摘要： Purpose This study aimed to investigate the relationship between the interferon-gamma (IFN-gamma) pathway in different tumor microenvironments (TME) and patients' prognosis, as well as the regulatory mechanisms of this pathway in tumor cells. Methods Using RNA-seq data from the TCGA database, we analyzed the predictive value of the IFN-gamma pathway across various tumors. We employed a univariate Cox regression model to assess the prognostic significance of IFN-gamma signaling in different tumor types. Additionally, we analyzed single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database to examine the distribution characteristics of the IFN-gamma pathway and explore its regulatory mechanisms, highlighting how IFN-gamma influenced cellular interactions within the TME. Results Our analysis revealed a significant association between the IFN-gamma pathway and adverse prognosis in pan-cancer tissues (P < 0.001). Interestingly, this correlation varied regarding positive and negative regulation across different tumor types. Through a detailed examination of scRNA-seq data, we found that the IFN-gamma pathway exerted substantial regulatory effects on stromal and immune cells. In contrast, its expression and regulatory patterns in tumor cells exhibited diversity and heterogeneity. Further analysis indicated that the IFN-gamma pathway not only enhanced the immunogenicity of tumor cells but also inhibited their proliferation. Cell-cell interaction analysis confirmed the pivotal role of the IFN-gamma pathway within the overall regulatory network. Moreover, we identified HMGB2 (high mobility group box 2) in T cells as a potential key regulator of tumor cell proliferation. Conclusions The IFN-gamma pathway exhibited a dual function by both suppressing tumor cell proliferation and enhancing their immunogenicity, positioning it as a pivotal target for refined cancer diagnosis and cancer strategies.

摘要： Host genetics shape immune responses and influence severity of infectious diseases. The HLA-B -21 M/T dimorphism tunes the functionality of natural killer (NK) cells expressing the inhibitory receptor NKG2A. NKG2A+ NK cells have been reported to recognize SARS-CoV-2-infected cells, but it remains unclear whether the HLA-B -21 M/T dimorphism associates with COVID-19 severity. Here, we investigated the influence of the HLA-B -21 M/T dimorphism in a cohort of 230 unvaccinated patients hospitalized with COVID-19 and requiring respiratory support. We found that HLA-B -21 M/M genotypes were more prevalent in patients with moderate compared to severe COVID-19 (6.0% vs. 0.9%). Comparison of age- and sex-matched sub-groups revealed that patients with M/M genotypes required mechanical respiratory support less frequently (OR = 0.13, 95% CI = 0.01-0.76, P = 0.013). Furthermore, patients with M/M genotypes showed a coordinately shifted signature of clinical laboratory parameters, coinciding with elevated serum levels of the anti-viral cytokine IFN-gamma. These findings demonstrate that HLA-B variants associate with COVID-19 severity and suggest that the robust functionality of NKG2A+ NK cells in patients carrying the M/M genotype may contribute to protection from severe disease.

关键词： Multiple myeloma   Autophagy   UPR   Adenovector   HSV-tk   GCV   IL-24  

摘要： Multiple myeloma is a type of malignant neoplasia whose treatment has changed over the past decade. This study aimed to investigate the effects of combination of Adenovector-carrying interleukin-24 and herpes simplex virus 1 thymidine kinase/ganciclovir on tumor growth, autophagy, and unfolded protein response mechanisms in mouse model of multiple myeloma. Six groups of mice, including Ad-HSV-tk/GCV, Ad-IL-24, Ad-HSV-tk/IL-24, Ad-GFP, and positive and negative controls, were investigated, and each group was injected every 72 h. The tumor size was measured several times. The expression of LC3B evaluated through western blotting and ASK-1, CHOP, Caspase-3, and ATF-6 genes in the UPR and apoptosis pathways were also analyzed by the quantitative polymerase chain reaction (qPCR) method. The present results showed that the injection of Ad-HSV-tk/GCV, Ad-HSV-tk/IL-24, and metformin reduced the tumor size. The expression of LC3B was significantly higher in the treatment groups and positive control groups compared to the negative control group. The expression of CHOP, caspase-3, and ATF-6 genes was significantly higher in the Ad-IL-24 group compared to the other treatment groups. Besides, the ASK-1 expression was significantly lower in the Ad-IL-24 group as compared to the other groups. Overall, the results indicated that the presence of the HSV-tk gene in the adenovectors reduced the size of tumors and induced autophagy by triggering the expression of LC3B protein. The presence of the IL-24 might affect tumor growth but not as much the therapeutic effect of HSV-tk. Furthermore, the results indicated that co-administration of IL-24 and HSV-tk had no synergistic effect on tumor size control.

关键词： IL-1   KSHV   lymphoma   PEL  

摘要： Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including primary effusion lymphoma (PEL), usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin-1 (IL-1) family is a major mediator for inflammatory responses and has functional role in both innate and adaptive immunity. We previously showed high activation of multiple IL-1 signaling molecules during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV-related malignancies. In the current study, we identified RP-54745, a potential antirheumatic compound as IL-1 inhibitor, effectively repressed KSHV + PEL cell growth through inducing tumor cell apoptosis. By using an established PEL xenograft model, we found that RP-54745 treatment suppressed tumor expansion in mice. Also, RP-54745 treatment significantly reduced hyperinflammation in tumor microenvironment including myeloid cells and neutrophils infiltration, as well as blocking IL-1 signaling molecules expression in vivo. In addition, our transcriptome analysis revealed novel cellular genes and mechanisms for anticancer activities of RP-54745. Taken together, our data indicate targeting IL-1 production and signaling may represent promising therapeutic strategies against these virus-associated diseases.

关键词： SARS CoV-2 infection   Lung transplant   HLA antibodies  

摘要： The purpose: The COVID-19 pandemic has led to significant morbidity and mortality in lung transplant recipients (LTR). Respiratory viral infections may be associated with de-novo HLA donor-specific antibody (DSA) production and impact lung transplant outcomes. Since one of the immunomodulation strategies post-SARS-CoV-2 infection in LTR include decreasing or holding anti-metabolites, concerns have been raised for higher incidence of de-novo DSA production in LTR. Methods: We performed a retrospective chart review of 63 consecutive LTR diagnosed with COVID-19 to investigate this concern. COVID-19 disease severity was divided into 3 groups: mild, moderate, and severe. Mild disease was defined as patients with COVID-19 diagnosis who were stable enough to be treated as out-patients. Moderate disease was defined as patients who required admission to the hospital and were on less than 10 l of oxygen at rest. Severe disease was identified as patients who required hospitalization and were on more than 10 l of oxygen with or without mechanical ventilation or extra corporal membrane oxygenation (ECMO). Groups were compared using the Kruskal-Wallis test. A total of 11, 43, and 9 LTR were diagnosed with mild, moderate, and severe COVID-19 respectively. Results: We observed no significant differences in the CPRA pre-COVID-19 compared to 1 and 6 months postCOVID-19 diagnosis in 6/11 (54.5 %), 18/43 (41.8 %), and 6/9 (66.9 %) LTR with mild (p = 0.66), moderate (p = 0.74), and severe (p = 0.22) COVID-19 respectively. HLA class I and II DSA were detected pre-COVID-19 diagnosis and persisted with no significant differences in the median MFI levels at 1 and 6 months postCOVID-19 diagnosis in 2/11 (p = 0.93), 7/43 (p = 0.71), and 0/9 LTR with mild, moderate, and severe COVID-19 respectively. De-novo HLA DSA were detected within 6 months post-COVID-19 diagnosis in 0/11 (0 %), 1/43 (2.3 %), and 3/9 (33.3 %%) LTR with mild, moderate, and severe COVID-19 respectively (p = 0.001). Conclusio

关键词： active immunotherapy   adjuvant-free   anti-cytokines   chronic inflammations   immunoengineering   self-assembly  

摘要： IL-1 beta is a principal proinflammatory cytokine underlying multiple local and systemic chronic inflammatory conditions including psoriasis, rheumatoid arthritis, inflammatory bowel disease, and type 2 diabetes. Passive immunotherapies and biologic drugs targeting IL-1 beta, while offering significant clinical benefit, nevertheless have limitations such as significant non-response rates, induction of anti-drug antibodies, and high costs. Here, an active immunotherapy raising antibody responses against IL-1 beta employing self-assembling peptide nanofibers is described. The nanofibers contain defined quantities of B-cell epitopes from IL-1 beta and exogenous T helper epitopes and employ the Q11 self-assembling peptide platform. Without adjuvant, the nanofibers raised durable anti-IL-1 beta antibody responses that inhibit IL-1 beta activity in vitro and in vivo. In a mouse model of imiquimod-induced psoriasis, prophylactic immunizations with the nanofibers diminished symptoms of epidermal thickening. This therapeutic effect is associated with biasing the immune response toward an anti-inflammatory IgG1/Th2 phenotype and a lowered expression of proinflammatory genes in the skin. Further, anti-IL-1 beta nanofibers induced therapeutic immunosuppressive CD62L+ Treg cells. This technology represents a potential alternative for passive immunotherapies and other biologics for treating chronic inflammatory conditions. Supramolecular peptide nanofiber immunogens are designed using B-cell epitopes from IL-1 beta and exogenous T-cell epitopes. Without adjuvant, these materials raise durable antibody responses that inhibit IL-1 beta activity in vitro and in vivo. In a mouse model of psoriasis, these immunizations diminish symptoms of epidermal thickening. This technology represents a potential alternative for anti-cytokine biologics for treating chronic inflammatory conditions. image

关键词： Pro-IL-1(3   Chicken   Monoclonal antibody   Detection   Antigenic epitope  

摘要： Pro-IL-1(3 is an important inflammatory factor and is also a biomarker for detecting early pro-inflammatory immune responses. However, commercially available antibodies against chicken inflammatory factors are lacking, which prohibits an in-depth exploration of the mechanism of chicken inflammation. This study cloned and expressed chicken pro-IL-1(3, and developed a hybridoma cell line 1E12 capable of stably secreting chicken pro-IL-1(3 monoclonal antibody (mAb). The secreted mAb 1E12 can recognize exogenous or endogenous chicken pro-IL-1(3 by Western blot and IFA techniques, and for the first time, a novel antigen epitope 13SSLSEETFY21 of chicken pro-IL-1(3 recognized by this mAb was identified. This study not only provides an important tool for the detection and research of chicken pro-IL-1(3, but also has significant implications for understanding the antigenic structure and biochemical characteristics of chicken pro-IL-1(3.

关键词： HLA   HLA-A*32:01:62   novel allele   sequencing-based typing  

摘要： HLA-A*32:01:62 differs from HLA-A*32:01:01:01 by one nucleotide substitution in codon 291 in exon 5.

关键词： allergic reactions   interleukin-4 receptor   miR-34a   molecular docking   Rocaglamide  

摘要： Rocaglamide (Roc-A), a natural phytochemical isolated from Aglaia species, is known to exert anticancer effects. Allergic inflammation can enhance the tumorigenic potential of cancer cells. We hypothesized that Roc-A could regulate allergic inflammation. Roc-A prevented an antigen from increasing the hallmarks of allergic reactions in vitro. Roc-A suppressed passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis (PSA). RNA sequencing analysis showed that Roc-A prevented the antigen from increasing the expression of IL-4 in RBL2H3 cells. Roc-A also prevented the antigen from increasing the expression of interleukin-4 receptor (IL-4R). Roc-A was found to form a hydrogen-bonding network with residues N92 and L64 of IL-4R in a molecular docking simulation. Roc-A prevented the antigen from inducing the binding of IL-4R to JAK1. Chromatin immunoprecipitation (ChIP) assays showed that C-Jun could bind to promoter sequences of IL-4 and IL-4R. Mouse recombinant IL-4 protein increased beta-hexosaminidase activity, IL-4R expression, and the hallmarks of allergic inflammation in the antigen-independent manner. Mouse recombinant IL-4 protein increased the expressions of CD163 and arghinase-1 and markers of M2 macrophages, but decreased the expression of iNOS, a marker of M1 macrophages in lung macrophages. Roc-A regulated the effects of a culture medium of antigen-stimulated RBL2H3 cells on the expressions of iNOS and arginase-1 in RAW264.7 macrophages. The blocking of IL-4 or downregulation of IL-4R exerted negative effects on the hallmarks of allergic reactions in vitro. The blocking of IL-4 or downregulation of IL-4R also exerted negative effects on PCA, and the downregulation of IL-4R exerted negative effects on PSA. An miR-34a mimic exerted negative effects on allergic reactions in vitro. The downregulation of IL-4R prevented the antigen from decreasing the expression of miR-34a in RBL2H3 cells. We identified chemicals that could bind to IL-4R via molecular do