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关键词： chronic obstructive pulmonary disease (COPD)   emphysema   percentage of low attenuation area (LAA%)   long non-coding interleukin-7 receptor alpha-subunit gene (lnc-IL7R)   machine learning  

摘要： Background/Objectives: Chronic obstructive pulmonary disease (COPD) remains a leading cause of death worldwide, with emphysema progression providing valuable insights into disease development. Clinical assessment approaches, including pulmonary function tests and high-resolution computed tomography, are limited by accessibility constraints and radiation exposure. This study, therefore, proposed an alternative approach by integrating the novel biomarker long non-coding interleukin-7 receptor alpha-subunit gene (lnc-Il7R), along with other easily accessible clinical and biochemical metrics, into machine learning (ML) models. Methods: This cohort study collected baseline characteristics, COPD Assessment Test (CAT) scores, and biochemical details from the enrolled participants. Associations with emphysema severity, defined by a low attenuation area percentage (LAA%) threshold of 15%, were evaluated using simple and multivariate-adjusted models. The dataset was then split into training and validation (80%) and test (20%) subsets. Five ML models were employed, with the best-performing model being further analyzed for feature importance. Results: The majority of participants were elderly males. Compared to the LAA% <15% group, the LAA% >= 15% group demonstrated a significantly higher body mass index (BMI), poor pulmonary function, and lower expression levels of lnc-Il7R (all p < 0.01). Fold changes in lnc-IL7R were strongly and negatively associated with LAA% (p < 0.01). The random forest (RF) model achieved the highest accuracy and area under the receiver operating characteristic curve (AUROC) across datasets. A feature importance analysis identified lnc-IL7R fold changes as the strongest predictor for emphysema classification (LAA% >= 15%), followed by CAT scores and BMI. Conclusions: Machine learning models incorporated accessible clinical and biochemical markers, particularly the novel biomarker lnc-IL7R, achieving classification accuracy and AUROC exceeding 75% in emp

关键词： Whole-body CT scanning radiation   Immune checkpoint inhibitor   NSCLC   Tumor microenvironment   IFN  

摘要： ObjectiveThe effect of frequent whole-body CT scans during immune checkpoint inhibitor (ICI) therapy on patients' anti-tumor *** conducted a retrospective clinical study aimed to investigate the correlation between the frequency of CT scans during immune checkpoint inhibitor (ICI) therapy and the duration of remission (DOR) of ICI therapy in patients with stage IV non-small cell lung cancer (NSCLC). We constructed a hormonal mouse model and administered immune checkpoint inhibitor (ICI) therapy to mice, and radiated five whole-body CT scans to mice during ICI therapy to observe whether frequent whole-body CT scans had an effect on the antitumor effect of immunotherapy in *** more frequent CT scans during patients' immune checkpoint inhibitor (ICI) treatment the longer the duration of remission (DOR) of ICI treatment. In a mouse model we observed that the addition of whole-body CT scanning radiation had a tendency to inhibit tumor growth in mice compared with the anti-PD-1 group *** CT scanning radiation during the application of immune checkpoint inhibitor PD-1 increased the proportion of infiltrating CD8 + T cells in tumor tissues and significantly increased the proportion of IFN gamma-secreting CD8 + T cells, and single-cell sequencing of the results also revealed that IFN gamma and killing-related genes were significantly upregulated in tumor-infiltrating CD8T *** our knowledge this is the first study on the effect of CT scan radiation on *** findings suggest that multiple CT scans during immune checkpoint inhibitor (ICI) treatment did not promote tumor progression, but instead a trend toward delayed tumor progression was observed.

关键词： CD4(+) T Cells   Viral Infection   IFN-gamma   B-cell Responses  

摘要： CD4(+) T cells play a critical role in supporting antiviral humoral and cellular immune responses. Although these responses often coexist, one can sometimes dominate at the expense of the other. For instance, lymphocytic choriomeningitis virus (LCMV) induces a strong cellular immune response but generates a suboptimal neutralizing antibody (nAb) response, hindering viral clearance and enabling persistent infection. Recent findings indicate that this skewed preference toward cellular immunity is determined already during the differentiation of CD4(+) T cells. Specifically, subcutaneous (s.c.) LCMV infection predominantly induces T-bet(+) T helper 1 (T(H)1) differentiation while largely neglecting T follicular helper (T-FH) differentiation, a key driver of humoral immunity. Here, we investigated the mechanisms responsible for this impaired T-FH differentiation. We found that T-bet(+) cells induced by s.c. LCMV infection are heterogeneous and encompass a terminally differentiated T(H)1 subset expressing Granzyme-B (GzmB) and a Tcf-1(+) subset that retains the potential for T-FH differentiation but that does not express CXCR5 and other mature T-FH markers. Interestingly, T cell-derived IFN-gamma facilitated the proliferation of the GzmB(+) subset and inhibited Tcf-1(+) cells' progression into T-FH. The suppression of T-FH cells by IFN-gamma was not directly mediated through CD4(+) T cells but rather involved another cell type, likely dendritic cells. Consistently, inhibition of IFN-gamma enabled robust T-FH differentiation, formation of germinal centers and increased antibody production. Our study provides novel insights into the mechanisms inhibiting nAb production in response to viruses and lays a foundation for the development of advanced vaccine strategies.

摘要： Malignant neoplasms arise within a region of chronic inflammation, which is a key factor in all aspects of tumorigenesis including initiation, proliferation, invasion, angiogenesis, and metastasis. IL-1 plays critical functions in tumor development by influencing the tumor microenvironment and promoting cancer progression. However, the mechanism of continuous activation of the IL-1-mediated inflammatory pathway in tumors has not been fully elucidated. This study provides a novel mechanism of the autocrine activation of IL-1 signaling in squamous cell carcinoma (SCC) through a novel oncoprotein, TSC-22 homologous gene-1 (THG-1, also known as TSC22D4). The RNA sequencing analysis revealed that THG-1 overexpression enhances the transcription of NF-kappa B targets including IL1A, IL1B, TNFA, and IL8. Furthermore, THG-1 knockdown reduced the responsiveness to IL-1 through the suppression of NF-kappa B nuclear translocation. To elucidate the mechanism, we focused on a THG-1 interacting protein, NRBP1. We found that NRBP1 facilitates the degradation of TNF receptor-associated factor 6 (TRAF6) through its E3 ubiquitin ligase activity. THG-1 bound to NRBP1 and suppressed the degradation of TRAF6. Furthermore, THG-1 knockdown reduced TRAF6 abundance and NF-kappa B activity in SCC cells. Public database analyses of head and neck SCC revealed that high expression of THG-1 is associated with the activation of the IL-1 and TNF pathways, which share TRAF6 in the signal transductions. Finally, THG-1 abundance in laryngeal SCC specimens is elevated in patients with recurrence. These results indicated that THG-1 drives the self-sufficiency of IL-1-mediated inflammatory pathway, which could contribute to the future diagnosis and immunotherapy of ***: An oncoprotein, THG-1/TSC22D4 activates the IL-1-mediated inflammatory pathway through the suppression of TRAF6 degradation, which mediates the continuous inflammation in tumors.

摘要： TNF alpha induces vascular permeability and plays an important role in inflammation. In addition, TNF alpha-induced vascular leakage is involved in the increased extravasation of nanoparticle-formulated chemotherapeutic drugs, improving drug delivery and subsequent tumor response. In this study, we uncovered a positive correlation between the presence of pericytes in the tumor-associated vasculature and TNF alpha-induced leakage and drug delivery, especially when drugs were encapsulated in nanoparticles. RNA sequencing and pathway analysis identified high expression of C-X-C motif chemokine ligand 10 (CXCL10) in TNF alpha-stimulated pericytes. In addition, TNF alpha increased CXCL10 protein production by pericytes in vitro. In animal studies, tumor types with vessels with high pericyte coverage showed enhanced permeability and extravasation of drugs encapsulated in nanoparticles following treatment with TNF alpha, which could be blocked with a CXCL10-neutralizing antibody. In contrast, tumors harboring vessels with low pericyte numbers did not display increased drug extravasation in response to TNF alpha. Lack of pericyte coverage could be compensated by coadministration of CXCL10. These findings reveal a mechanism by which TNF alpha induces CXCL10 release from pericytes, resulting in increased endothelial permeability, vascular leakage, and drug ***: TNF alpha stimulates tumor-associated pericytes to produce CXCL10 that mediates vascular leakage and assists in the intratumoral delivery of nanoparticle-encapsulated chemotherapeutic drugs.

关键词： IL-33   Decitabine   Melanoma   Immune checkpoint blockade   Tumor microenvironment   Tumor-immune crosstalk   DNA methylation   In vivo models   Organ-on-chip  

摘要： BackgroundIL-33 is an epithelial-derived alarmin with various roles in cancer. In melanoma, endogenous and exogenous IL-33 exert anti-tumor effects through the stimulation of several immune effector cells. In this study, we explored the combination of IL- 33 with Decitabine (DAC), a DNA methylation inhibitor that promotes immune recognition by re-activating silenced genes, for melanoma *** spheroids, organ-on-chip technology and in vivo models were used to test the anti-tumor effects of IL-33 combined with DAC against mouse and human melanoma. Mice deficient for the IL-33 receptor ST2 (ST2-/- mice) were employed to address the role of endogenous IL-33 signaling in DAC therapeutic response and tumor-immune *** multicellular spheroids of mouse and human melanoma cells, DAC alone inhibited tumor cell aggregation, suggesting its direct effect on tumor cells. In vivo, DAC combined with IL-33 reduced tumor growth and prolonged the survival of mice transplanted with melanoma cells, outperforming single treatments. Moreover, the combined DAC/IL-33 treatment was the most efficient in promoting immune recruitment (i.e., T cells and eosinophils) at the tumor site and induced the up-regulation of PD-1 resulting in better therapeutic response to PD-1 blockade in vivo. In a microfluidic-based competitive migration assay, DAC/IL- 33 treatment generated the strongest chemotactic response, attracting spleen cells from na & iuml;ve wild-type, but not ST2-/- mice, indicating that IL-33 signaling was crucial for immune cell recruitment. Accordingly, DAC failed to induce tumor immune infiltration and was ineffective in reducing tumor growth in ST2-/- mice. In vivo, DAC increased the expression of ST2 and IL-33 at the tumor site, suggesting it may enhance endogenous IL-33 production. Methylation studies indicated that DAC increased the expression of IL-33 in mouse and human melanoma cells through demethylation of a transcription factor binding s

关键词： Ankylosing spondylitis   HLA-B*27 gene   Rapid detection   BASIS isothermal amplification   CRISPR/Cas12a  

摘要： Ankylosing spondylitis (AS) is a chronic, inflammatory arthritis of the spine and peripheral joints which is known to have a strong association with the human leukocyte antigen B27 (HLA-B27). Quantitative real-time PCR and flow cytometry are the predominant methods for HLA-B27 gene and antigen, respectively, which are too time-consuming and labor-intensive to realize rapid analysis. Therefore, a rapid diagnostic tool is highly required. In this study, we developed a rapid HLA-B*27 detection platform (namely BASIC) by combining our previously invented BASIS isothermal amplification method with the widely used CRISPR/Cas12a signal output tool. The BASIS can efficiently amplify all HLA-B*27 genotypes by using a set of universal primers, which target the conserved regions. The amplicons are subsequently applied to CRISPR/Cas12a analysis. The CRISPR/Cas12a recognizes the pathogenic HLA-B*27 amplicons specifically by using a well-designed gRNA, thereby achieving fluorescence signal output. Our results showed that the BASIC can be completed in 1 h with analytical sensitivity up to 100 aM. It could resist interference of homologous genes, hemoglobin, bilirubin, and triglyceride. For clinical sample detection, the BASIC offered completely consistent results with qPCR. Given the advantages of sensitivity, specificity, simplicity and rapidity, the BASIC was demonstrated a promising HLA-B*27 gene rapid detection tool for the early screening and diagnosis of AS.

摘要： Human induced pluripotent stem cells (iPSCs) offer a promising source for chimeric antigen receptor (CAR)-engineered natural killer (NK) products. However, complex iPSC-NK (iNK) manufacturing challenges clinical use. Here, we identified LiPSC-GR1.1 as a superior iPSC line for iNK production. By engineering LiPSC-GR1.1 with a mesothelin (MSLN)-targeting CAR and interleukin-15 (IL-15), we achieved robust differentiation of iPSCs into mature activated iNK cells with enhanced tumor killing efficacy, superior tumor homing, and vigorous proliferation. Single-cell transcriptomic analysis revealed that transforming growth factor-beta (TGF-beta)-producing tumor cells up-regulated major histocompatibility complex molecules and down-regulated MSLN post-CAR-IL-15 iNK treatment. Tumor-infiltrating CAR-IL-15 iNK cells exhibited high levels of CAR, IL-15, and NK-activating receptors, negligible checkpoint exhaustion markers, and extremely low levels of NK suppressive factors CISH, TGFBR2, and BATF, enabling them to sustain activation, metabolic fitness, and effective tumor killing within TGF-beta-rich hypoxic tumor microenvironment. Overall, we developed ***-IL-15-engineered GR1.1-iNK therapy with enhanced antitumor efficacy for solid tumor treatment.

关键词： ferroptosis   glycolysis   HIF-1 alpha   IL-10R alpha   MOF   osteoarthritis  

摘要： Osteoarthritis (OA) is a low-grade inflammatory disease that is highly associated with severe hyperplasia of the synovial membrane and the degeneration of cartilage. Interleukin-10 (IL-10), has been extensively studied, while its receptor, IL-10R alpha, has not been widely mentioned in the context of OA. A significant difference is found in the expression of IL-10R alpha in synovial macrophages from normal and OA patients, along with a marked increase in the glycolytic activity of synovial macrophages. In IL-10R alpha Lysm OA mice, the specific deficiency of IL-10R alpha exacerbated the progression of OA. Mechanistically, hypoxia-inducible factor-1 alpha (HIF-1 alpha) is identified as a key transcription factor, and its inhibition significantly weakened the glycolytic process. Additionally, differences in ferroptosis of chondrocytes are observed. After co-culturing the two types of cells in vitro, a significant connection is found between the glycolytic state of synovial macrophages and the ferroptosis of chondrocytes. To achieve targeted therapy, MI@UN, a biomimetic nanoparticle encapsulating NO-prednisolone in UIO-66-NH2, surface-modified with IL-10, and coated with macrophage membranes (MM), is developed. It significantly slows osteoarthritis progression in mice. This offers new insights into OA pathogenesis, highlighting IL-10R alpha as a therapeutic target and supporting MI@UN's translational use for OA treatment.