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关键词： IL-35   Immune evasion   Tumor microenvironment   iTr35  

摘要： Dendrobium huoshanense has received special attention for its advantages in the treatment of lung cancer, but the underlying molecular mechanisms are not yet well understood. First, we obtained 8 active ingredients and 159 effective action targets of Dendrobium huoshanense using network pharmacology, and searching target interactions through STRING, constructing the PPI network and KEGG, GO and Hallmark enrichment analysis. Then, we combined target's enrichment analysis and GSEA enrichment analysis of IL-35, indicating the mechanism of cDHPs for non-small cell lung cancer (NSCLC) may be related to tight junction and NSCLC pathway. Further, FXR1 and ACTR3 were identified as core therapeutic targets, and high expression of FXR1 or ACTR3 was significantly associated with poor prognosis of patients. The analysis of single-cell data also indicated that the percentage of CD4-CTLA4-Treg cells may be increased by the expression of IL-35, resulting in a suppressive immune microenvironment. Next, In vivo experiment, we detected iTr35 by flow cytometry, detected IL-35 level by RT-PCR, Western blotting and ELISA, and detected NK cell activity to explore the immunomodulatory effects and anti-tumor mechanism of cDHPs. After cDHPs administration, the conversion of CD4 T cells to iTr35 is inhibited, p35 and EBI3 in both protein and mRNA levels, the levels of IL-35 and IL-4 in serum decreased. The levels of IFN-γ, while the activity of NK cells in mice increased, enhancing the anti-tumor immune effect of the organism. Finally, analysis of sequencing data from the immunotherapy cohort of tumor-bearing mice obtained from the TISMO database shows that the combination of cDHPs and PD-1/PD-L1 antibodies improves effector and thus PD-1/PD-L1 antibody efficacy. These findings suggest that cDHPs inhibit NSCLC proliferation and immune escape via the FXR1-IL-35 axis signaling pathway.

关键词： Behçet's disease   HLA‐B51   clinical manifestations   gender differences   genetics  

摘要： HLA-B51 is well-established as a genetic risk factor for the development of Behçet's disease (BD), and its association with certain clinical manifestations has been documented. However, there is a lack of comprehensive research examining its role in the overall symptom completeness and full clinical expression of the disease. We performed a retrospective review of medical records from 1203 patients treated at a tertiary hospital between June 2012 and June 2017. Data regarding HLA-B51 status and clinical conditions were extracted, and patients were classified according to the "Revised Japanese Diagnostic Criteria for Behçet's disease (1987)", resulting in 878 patients diagnosed with complete (n = 250) and incomplete (n = 628) BD. Among these patients, 400 (45.6%) were tested positive for HLA-B51, with the positivity rate progressively increasing with the severity of symptoms. Male patients exhibited a higher likelihood of HLA-B51 positivity (61.9%) and a greater prevalence of skin and ocular symptoms, while female patients showed a higher incidence of erythema nodosum (42.2%) and genital ulcers (91.0%). Notably, a positive correlation was observed between skin lesions and genital ulcers, whereas ocular symptoms demonstrated a negative correlation with both skin and genital manifestations. This study underscores the significant impact of HLA-B51 positivity on the clinical presentation of BD. Insights gained from this research can enhance our understanding of genetic influences on symptom expression, ultimately leading to diagnostic and therapeutic approaches for patients with the disease.

摘要： BACKGROUND:Patients awaiting a solid organ transplant require pretransplant testing including high-resolution HLA typing and screening of HLA antibodies. However, the standard HLA antibody testing cannot encompass all the HLA alleles available in the Australian donor pool. With the advent of high-resolution HLA typing for organ allocation, there is an increased prevalence of detecting uncommon HLA alleles. It is challenging to manually determine whether patients have donor-specific HLA antibodies against these antigens. To address this issue, a bioinformatic pipeline, HLA-EP-RESOLVER, was developed to assess eplet reactivity for rare HLA unacceptable antigens (UAs). METHODS:The HLA-EP-RESOLVER pipeline was validated against sensitized patients, and a list of candidate UAs was identified for each patient. The candidate UAs must meet the following criteria: (1) match at the first field with existing UAs, (2) share eplets or serological types with the current UAs, (3) do not share the patient's self-eplets or eplets on negative beads, and/or (4) in the exception rules. The Australian deceased donor pool was used as the initial model. The predicted UAs were then confirmed with physical crossmatching. RESULTS:The pipeline proved to be highly accurate at predicting high-risk antigens by utilizing eplet analysis through HLA Matchmaker, and the HLA data extracted from the Australian donor population. The reactivity of several candidate UAs were confirmed by cellular verification. CONCLUSIONS:The HLA-EP-RESOLVER program was shown to be rapid, useful, and highly accurate in determining acceptable or unacceptable HLA alleles in the new era of rapid high-resolution donor typing before allocation.

关键词： Epstein-Barr virus-associated NK-cell lymphoproliferative diseases   Hemophagocytic lymphohistiocytosis   IL-10   KLRs   LINC02446   Long non-coding RNA  

摘要： INTRODUCTION:Refractory Epstein-Barr virus-associated NK-cell lymphoproliferative diseases (EBV-NK-LPDs) are prone to hemophagocytic lymphohistiocytosis (HLH) with short survival and poor prognosis. Although various therapies have been used to relieve the symptoms, hematopoietic stem cell transplantation is considered the only potentially therapeutic approach. There is an urgent need to explore the pathogenesis of EBV-NK-LPDs and develop an effective better treatment. METHODS:Here, we investigated long non-coding RNA (lncRNA) profile using high-throughput RNA sequencing data (n = 6, healthy donors; n = 5, infectious mononucleosis; n = 10, chronic active Epstein-Barr virus disease (CAEBV)-NK; n = 7, CAEBV-T) and screened out LINC02446, whose upregulation was further validated by quantitative real-time polymerase chain reaction in EBV-NK-LPDs. We further explored the correlation between LINC02446 and the clinical characteristics of patients with EBV-NK-LPDs. Then, based on sequencing data, we performed in vitro experiments to investigate the function and mechanism of LINC02446 in EBV-NK-LPDs. RESULTS:LINC02446 was specifically highly expressed in NK cells of EBV-NK-LPDs patients. EBV-NK-LPDs patients with high expression of LINC02446 showed higher EBV-DNA copy number and ferritin levels, as well as a higher incidence of HLH. LINC02446 was closely related to the KLRs family and LINC02446 could regulate the expression of KLRs genes. In addition, LINC02446 positively regulated the expression of IL-10 in EBV-NK-LPDs cell lines, which revealed that LINC02446 may promote HLH by upregulating IL-10 in EBV-NK-LPDs. CONCLUSIONS:This is the first study that LINC02446 regulates the expression of KLRs family and IL-10 in EBV-NK-LPDs, resulting in lymphoma progression and HLH occurrence, showing its potential as a therapeutic target for EBV-NK-LPDs.

关键词： Anti-IL-13   Anti-IL-4   Asthma, airway remodeling   Interlukin-13 (IL-13)   Interlukin-4 (IL-4)  

摘要： Asthma is a chronic respiratory disorder affecting individuals across all age groups. It is characterized by airway inflammation and remodeling and leads to progressive airflow restriction. While corticosteroids remain a mainstay therapy, their efficacy is limited in severe asthma due to genetic and epigenetic alterations, as well as elevated pro-inflammatory cytokines interleukin-4 (IL-4), interleukin-13 (IL-13), and interleukin-5 (IL-5), which drive structural airway changes including subepithelial fibrosis, smooth muscle hypertrophy, and goblet cell hyperplasia. This underscores the critical need for biologically targeted therapies. This review systematically examines the roles of IL-4 and IL-13, key drivers of type-2 inflammation, in airway remodeling and their potential as therapeutic targets. IL-4 orchestrates eosinophil recruitment, immunoglobulin class switching, and Th2 differentiation, whereas IL-13 directly modulates structural cells, including fibroblasts and epithelial cells, to promote mucus hypersecretion and extracellular matrix (ECM) deposition. Despite shared signaling pathways, IL-13 emerges as the dominant cytokine in remodeling processes including mucus hypersecretion, fibrosis and smooth muscle hypertrophy. While IL-4 primarily amplifies inflammatory cascades by driving IgE switching, promoting Th2 cell polarization that sustain cytokine release, and inducing chemokines to recruit eosinophils. In steroid-resistant severe asthma, biologics targeting IL-4/IL-13 show promise in reducing exacerbations and eosinophilic inflammation. However, their capacity to reverse established remodeling remains inconsistent, as clinical trials prioritize inflammatory biomarkers over long-term structural outcomes. This synthesis highlights critical gaps in understanding the durability of IL-4/IL-13 inhibition on airway structure and advocates for therapies combining biologics with remodeling-specific strategies. Through the integration of mechanistic insights and

关键词： Head and Neck Cancer   Human leukocyte antigen - HLA   Immune modulatory   Major histocompatibility complex - MHC  

摘要： BACKGROUND:Adenoid cystic carcinoma (ACC) is a rare, but lethal cancer with low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite extensive clinical trials, no effective treatments for patients with recurrent or metastatic ACC are available, and ACC mortality rates remain poor. METHODS:We employed automated multiplex immunofluorescence (mIF), single-cell RNA sequencing (scRNA-seq) Gene Expression analysis, RNA in-situ hybridization, and spatial transcriptomics analysis to characterize the immune landscape of ACC tumors, ACC metastasis, and normal tissues from regions where ACCs arise. Based on results from these studies, we treated freshly resected ACCs with interferon-γ or a stimulator of the interferon genes (STING) agonist in vitro. Additionally, we included one patient with ACC in a phase 1 clinical study of a novel STING agonist (dazostinag) plus pembrolizumab. RESULTS:The mIF analysis revealed that ACC tumors are immunologically "cold", with few tumor-infiltrating T-lymphocytes and low programmed death-ligand 1 (PD-L1) expression. The most striking finding was a very low beta-2-microglobulin (B2M) expression in nearly all ACCs, with only focal expression found in some ACC metastases. mIF and RNA sequencing analyses of normal salivary gland and breast tissues revealed a p63+, NFIB+, basal duct cell population, with similarly low B2M/human leukocyte antigen (HLA) class I expression. Spatial transcriptomics analysis of the focally B2M-positive ACC metastases uncovered the genetic pathway driving upregulation of B2M, an interferon-γ program mediating the reintroduction of HLA-I/B2M; the significantly upregulated genes included and . On short-term treatment of primary ACC tissues in vitro with interferon-γ or a STING agonist, we observed strongly upregulated HLA class I/B2M expression. Moreover, treatment of a patient with recurrent, metastatic breast ACC with a STING agonist and pembrolizumab led

摘要： BackgroundTumor-associated macrophages (TAMs) in the tumor microenvironment (TME) primarily polarize into the M2-phenotype. Our previous study showed that the small GTPase Rab37 mediates IL-6 trafficking in macrophages for M2 polarization. Here, we uncover an unconventional role of Rab37, independent of vesicle trafficking, in promoting M2 polarization of *** gene profiles in wild-type and Rab37 knockout (KO) bone marrow-derived macrophages (BMDMs) were analyzed using cDNA microarray. The mechanism of Rab37 in regulating the interferon (IFN) pathway was confirmed through in vitro/vivo assays and clinical *** I IFN signaling was highly enriched in BMDMs from Rab37 KO mice. Moreover, Rab37 induction and decreased type I IFN genes were observed in macrophages treated with lung cancer-conditioned medium and epigenetic drugs, indicating an epigenetic regulation of Rab37 in TAMs. Mechanistically, GDP-bound Rab37 interacted with the nuclear localization sequence of STAT1 to sequest it in the cytosol from its transcription activities, thus leading to the downregulation of IFN genes. Clinically, CD163+/Rab37+/STAT1cytosol in TAMs expression signature correlated with advanced tumor stages and poor survival of lung cancer *** findings highlight the cytosolic interaction of Rab37-STAT1 in M2 TAM polarization, with CD163+/Rab37+/STAT1cytosol TAMs as a lung cancer prognosis biomarker.

关键词： DFT and MD simulations   PPI networking   RA   TNF-α   Virtual screening  

摘要： In humans, rheumatoid arthritis (RA) is a deadly autoimmune disease that affects bone health. Although the specific etiology of RA is unknown, scientific evidence suggests that smoking, genetic abnormalities, and environmental factors may all contribute to the disease's progression. We employed protein-protein interaction (PPI) networking analysis to identify a possible therapeutic target for RA. The lead-like molecule for the selected target was then found via virtual screening in the Indian medicinal plants phytochemistry and therapeutics database. Molecular dynamics has confirmed the stability of drug target-lead-like molecule complexes. The networking analysis identifies TNF-α as a potential therapeutic target for RA. TNF-α expression was verified using in vitro studies. Cassamedine was identified as a possible lead molecule among 17,967 chemicals in the Indian Medicinal Plants Phytochemistry and Therapeutics database using virtual screening experiments. The molecular docking results of the lead compound interaction with TNF-α were clarified by the quantum mechanism (QM) technique, namely, density functional theory (DFT). The stability of the lead-like compound with TNF-α was confirmed using 200 ns of molecular dynamics simulations. Energy calculations using molecular mechanics Poisson-Boltzmann surface area (MMPBSA) confirm the free energy between TNF-α and lead-like molecules.

摘要： To investigate the differences in HLA-I antibody distribution and corresponding platelet transfusion effectiveness among patients with a history of platelet transfusion refractoriness(PTR) in the Han population of Zhejiang, China, to ensure the rational utilization of platelet resources.A retrospective analysis was conducted on 77 patients with a history of PTR admitted to the Hematology Department of Zhejiang Provincial Hospital of Traditional Chinese Medicine from May 2018 to December 2022. Testing was conducted for HLA-I antibodies in platelets were tested using an immune microsphere liquid chip. The distribution of antibodies and their intensities were analyzed along with the distribution characteristics of antibodies by disease type, sex, age, and blood type. Furthermore, the relationships between HLA-I antibody intensity distribution and transfusion frequency, as well as transfusion outcomes, were *** average positive rates of HLA-A, -B, and -C antibodies were 0.393, 0.527, and 0.242. The number of weakly positive and total positive HLA-I antibodies in the ITP group was significantly lower than in the other disease categories (P < 0.05).Positive HLA-I antibody count was not related to the patient’s sex, blood type, or age. In contrast, positive HLA-I antibody count was significantly higher for platelet transfusions > 10 than for platelet transfusions ≤ 10. As anticipated, the effectiveness of HLA standard antigen-matched platelet transfusions was significantly superior to random platelet transfusions (P < 0.001).The distribution of HLA-I antibodies in PTR patients among the Han Chinese population in Zhejiang, China is relatively extensive. An increase in the frequency of platelet transfusions leads to higher frequency and stronger intensity of HLA-I antibody production, resulting in poorer transfusion outcomes. HLA standard antigen-matched platelet transfusions can effectively address the occurrence of PTR.