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关键词： Arg1 macrophages   CP: Cancer   CP: Immunology   DNA methylation   EP2   MHC-II macrophages   lung metastasis   macrophage differentiation   monocyte-to-macrophage transition   prostaglandin E(2)   tumor-associated macrophage  

摘要： Monocytes differentiate into macrophages (Mφs) to facilitate lung metastasis, but the monocyte-to-Mφ transition during this process is not well understood. To investigate, we performed bulk RNA sequencing on Mφs isolated from the lungs of mice bearing Lewis lung carcinoma tumors and from naive lungs. Our results showed impaired differentiation of monocytes into major histocompatibility complex (MHC) class II Mφs, with an upregulation of PGE-inducible genes, including Arg1, in tumor-associated Mφs (TAMs). In vitro experiments confirmed that prostaglandin E (PGE) inhibits the differentiation of MHC class II Mφs while promoting Arg1 Mφs via the E prostanoid 2 (EP2) receptor, accompanied by DNA methylation. Whole-genome bisulfite sequencing revealed that PGE-EP2 signaling drives the hypermethylation and downregulation of gene sets related to myeloid cells in non-neoplastic tissues. Our study highlights PGE-EP2-driven DNA methylation in the monocyte-to-TAM transition, suggesting potential therapeutic avenues for lung metastasis.

关键词： IL2Ra   Rib fractures   acute kidney injury   acute lung injury   inflammation  

摘要： BACKGROUND:Rib fractures compromise approximately 40% of all fractures in the United States. Despite their prevalence, the relationship between rib fractures, solid organ injuries, and immune responses remains poorly understood. This exploratory study investigates the immunological profile associated with pulmonary and renal complications in rib fracture patients using data from our Surgical Critical Care Initiative Clinical Data Repository. The aim is to correlate distinct cytokine/chemokine profiles with high-energy rib fracture patterns, such as first rib fracture, and associated complications, potentially providing predictive biomarkers for patient outcomes. METHODS:Clinical and demographic data on patients with rib fractures were extracted from Surgical Critical Care Initiative Clinical Data Repository. Patients were categorized based on the presence or absence of complications. A comprehensive panel of 46 inflammation and tissue repair biomarkers was measured using the Meso Scale Discovery platforms. Principal component analysis was used to reduce the dimensionality of the cytokine data. Statistical and machine learning models assessed the association between biomarker patterns, rib fracture localization, and complications. Logistic regression models with high discriminative performance were developed for first rib fractures (high energy transfer), lung injury, and pneumonia. RESULTS:Among 150 rib fracture patients, 73 had complications. Cytokine analysis revealed two distinct clusters: Cluster 1, associated with pro-inflammatory responses and tissue repair, and Cluster 2, linked with anti-inflammatory responses, angiogenesis, and immunometabolism. Predictive models demonstrated strong validity (area under the curve, >0.90) and identified key variables such as the cytokine IL2Ra, significantly associated with acute kidney injury, acute lung injury, and pulmonary complications post-rib fractures, particularly first rib fractures. CONCLUSION:IL2Ra release is sig

关键词： Dexamethasone   Inflammatory pathway   Phosphodiesterase-4   Roflumilast  

摘要： INTRODUCTION:High-dose dexamethasone (DEX) is used for management of severe conditions. However, the multisystem adverse effects induced by glucocorticoids represent a hindering stone toward the effective clinical use of such agents. Various initiatives have been taken to ameliorate these complications with limited success. AIM:The present study aims to explore the beneficial effects of roflumilast (ROF), a phosphodiesterase-4 (PDE-4) inhibitor, to combat DEX-induced steatohepatitis, metabolic abnormalities and aortic degeneration. RESULTS:The application of ROF (2.5 and 5 mg/kg) has reverted the hepatic and aortic histopathological abnormalities as well as the rise in serum liver enzymes induced by DEX. Such palliative effect is probably attributed to PDE-4 inhibition (↑cAMP) that subsequently regulates multiple effectors. The chemotaxis of inflammatory cells (MCP-1) was inhibited by ROF treatments which was linked to inhibition of extracellular ROS production (MDA and NO) as well as restoration of cellular antioxidant defense (GSH). DEX challenge was associated with activation of the inflammatory pathways including TNF-α/NF-κB and NLRP3/IL-1β that were significantly dampened in the ROF groups. The oxidative stress as well as activation of inflammatory pathways exerted by DEX has contributed to the activation of endoplasmic reticulum stress (CHOP and PERK) posing more threats to the insulted cells, however, fortunately, ROF treatments showed inhibited activation of ER stress sensors and thereby abstaining the cells from inevitable damage. The metabolic abnormalities induced by DEX including elevated fasting insulin and heightened AUC of blood glucose level upon application of oral glucose tolerance test were significantly improved by ROF treatment. CONCLUSION:The findings of our study depicted the hepatoprotective and metabolic regulating potentials of ROF in a rat model of DEX- induced steatohepatitis. Thereby, enhancing the overall efficacy and safety of DEX use

关键词： Biomarker   Immunosuppression   MHC   Pancreatic Cancer   Prognosis  

摘要： The low immunogenicity of pancreatic cancer inhibits effective antitumor immune responses, primarily due to the immune evasion mediated by low expression of the major histocompatibility complex (MHC). Through comprehensive analysis, our study identifies UPK3B as a gene closely associated with low MHC expression and low immunogenicity in pancreatic cancer. UPK3B has been reported as a marker of primary mesothelial cells, mature epicardium and promotes extracellular matrix signaling. However, the role of UPK3B in pancreatic cancer remain unclear. We found that UPK3B is highly predictive of overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC) and is significantly related to clinical features, immune cell infiltration, and response to immune checkpoint inhibitor (ICI) therapy. Gene enrichment analysis revealed significant downregulation of immune regulatory and BCR signaling pathways in the UPK3B high-expression group. Additionally, UPK3B is positively correlated with immunosuppressive cells, suggesting that high UPK3B expression may inhibit antitumor immune responses by promoting low MHC expression. UPK3B is also positively correlated with immune checkpoints, indicating that tumors with high UPK3B expression may not benefit from ICI therapy. Therefore, UPK3B may serve as a novel biomarker and therapeutic target for pancreatic cancer.

关键词： HLA   PD‐L1   immune checkpoint inhibitor   lymphocyte   oral cancer  

摘要： Oral squamous cell carcinoma (OSCC) is one of the most common head and neck cancers, and immunotherapy targeting programmed cell death 1 (PD-1) has become a treatment option for recurrent OSCC after surgery and radiation therapy. However, few studies have identified definitive biomarkers for predicting patient response to anti-PD1 therapy in OSCC. In the present study, biopsy specimens were obtained from 23 patients with recurrent OSCC who were subsequently treated with anti-PD1 therapy. Immunohistochemical examinations of CD3, CD8, FOXP3, CD103, CD163, programmed cell death ligand 1 (PD-L1), HLA-A/B/C, HLA-DR, and β2 microglobulin were performed, and their correlation with clinical response was statistically analyzed. We found that an increased density of CD8-positive lymphocytes and increased PD-L1 expression predicted a favorable response to anti-PD1 therapy in recurrent OSCC. In contrast, clinical factors such as age and sex, and immune-related factors such as HLA-Classes I and II, were not associated with the response to anti-PD1 therapy. Taken together, our results suggest that immunohistochemical analysis of CD8 and PD-L1 may be useful for predicting the efficacy of anti-PD1 therapy in recurrent OSCC.

关键词： COVID-19   Common side effects   GWAS   HLA   MHC locus   Vaccination  

摘要： Individual differences have been observed in side effects after vaccination for COVID-19, and host genetic factors have been suggested as a contributing factor. Here, we conducted a genome-wide association study (GWAS) involving 2,554 Japanese corporate employees who received a third booster dose of BNT162b2/Pfizer or mRNA-1273/Moderna vaccine. Although no genome-wide significant association was found for the presence of adverse symptoms, the GWAS for severity revealed six associated loci. The most significant association was observed between the severity of swelling of lymph nodes and chromosome 2q12 locus, including the IL1RL1, IL18R1, and IL18RAP genes (lead variant: rs76152249; P = 1.46 × 10). Pathway analysis suggested associations between immune pathways related to the MHC locus, including HLA genes, and the occurrence and severity of fever, and the NF-κB binding pathway and those of itching at the injection site. In addition, a meta-analysis of previous GWAS studies for the primary first or second dose of COVID-19 vaccine revealed 818 variants from 72 loci that demonstrated genome-wide significant associations with any of 12 symptoms, and pathway analysis identified immune pathways related to the MHC locus, suggesting shared genetic risks among primary and booster vaccinations. These results may help control side effects following COVID-19 vaccination.

关键词： CSF IL-6   CSF PCT   Cell index   Intracranial infection   Post-neurosurgery  

摘要： This study evaluated the predictive value of cell index (CI), cerebrospinal fluid procalcitonin (CSF PCT), and cerebrospinal fluid interleukin-6 (CSF IL-6) for detecting intracranial infection after neurosurgery. A two-center, prospective study analyzed CSF samples from ICU patients suspected of having intracranial infection following neurosurgery from January 2020 to June 2023. Patients with infection had longer operation times and longer stays in the ICU. The AUCs for single biomarkers ranged from 0.829 to 0.860, with the highest AUC of 0.938 observed for the combined biomarkers CI + CSF PCT + CSF IL-6. CI was most effective in patients with elevated CSF RBC counts, and PCT was most effective for detecting Gram-negative infections. The combined use of these biomarkers enhances early diagnosis of intracranial infection after neurosurgery and warrants further study.

关键词： IL-6   Laryngeal squamous cell carcinoma   MCTS1   Non-coding RNA   Tumor microenvironment   circHIPK2   miR-889–3p  

摘要： Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor of the head and neck with a poor prognosis. The role of circRNAs in LSCC remains largely unknown. In this study, quantitative real-time PCR (qRT-PCR), Sanger sequencing and fluorescence in situ hybridization were undertaken to detect the expression, localization, and clinical significance of circHIPK2 in LSCC tissues and TU686 and TU212 cells. The functions of circHIPK2 in LSCC were explored through proliferation analysis, EdU staining, colony formation assay, wound healing assay, and Transwell assay. The regulatory mechanisms underpinning circHIPK2, miR-889-3p, and MCTS1 were investigated using luciferase assay, Western blotting, and qRT-PCR. We found that LSCC tissues and cells demonstrated high expression of circHIPK2 that was closely associated with the malignant progression and poor prognosis of LSCC. Knockdown of circHIPK2 inhibited the proliferation and migration of LSCC cells in vitro. Mechanistic studies showed that circHIPK2 competitively bound to miR-889-3p, elevated MCTS1 level, promoted IL-6 secretion, and ultimately accelerated the malignant progression of LSCC. In conclusion, an axis involving circHIPK2, miR-889-3p, MCTS1 and IL-6 regulates the malignant progression of LSCC. circHIPK2 expression may serve as a novel diagnostic and prognostic biomarker for LSCC.

关键词： Crossmatch   HLA-DQ   Luminex   Phenotype antigen   Single antigen  

摘要： De novo donor-specific HLA-DQ antibodies detected by single antigen beads (SAB) are significantly associated with chronic antibody-mediated rejection and lower overall graft survival. However, some DQ antibodies identified by SAB cannot be confirmed by phenotype antigen-bearing Class II bead assays, raising concerns about the validity of SAB data. The inability to detect these antibodies on phenotype antigen beads could be due to a lower quantity of DQ antigens present on the surface of the beads compared to DR antigens. In this study, we demonstrate that DQ-enriched phenotype antigens exhibit the same reactivity with DQ antibodies detected by SAB, confirming the hypothesis that it is antigen quantity and, not structural differences, that account for discrepancies in HLA DQ antibody detection between phenotype antigen beads and SABs. In addition, we show that the expression of individual DQ antigens in heterozygous cells can vary significantly, further confounding correlation studies. Therefore, the common clinical practice of using the phenotype antigen beads as a screening assay, reflexing to SAB testing only when positive, may inadvertently fail to detect DQ-specific antibodies. Such errors could impact organ acceptance practices, immunosuppression treatment decisions and/or the need for additional diagnostic testing to rule out antibody-mediated rejection.

关键词： Endometrial tissue   Endometriosis   IL-17   PBMCs   T(H)17 cells  

摘要： Endometriosis, an inflammatory disease, is characterized by the aberrant presence of endometrial tissues at ectopic locations. Accumulating evidence suggests that inflammatory cells, such as interleukin-17 (IL-17)-producing cells, may be involved in the pathogenesis of endometriosis. This investigation assessed the frequency of IL-17A (commonly known as IL-17)-producing cells in peripheral blood mononuclear cells (PBMCs), ectopic, and eutopic endometrial tissues in patients with endometriosis compared to non-endometriotic subjects. PBMCs, ectopic, and eutopic endometrial tissues were collected from 23 patients with endometriosis. PBMCs and endometrial tissues from 20 non-endometriotic women were used as the control group. The frequency of T helper 17 (T17) lymphocytes in PBMCs was assessed using flow cytometry, and the expression level of IL-17 in eutopic and ectopic endometrial tissues was evaluated through immunohistochemistry. The percentage of T17 and IL-17-producing lymphocytes was significantly higher in the PBMCs of patients with endometriosis compared to non-endometriotic subjects (P < 0.01 and P < 0.001, respectively). The expression of IL-17 protein in ectopic (P < 0.001) and eutopic (P < 0.05) endometrial tissues of patients with endometriosis increased compared to controls' endometrial tissue. Furthermore, the eutopic endometrium of patients with endometriosis showed a higher expression of IL-17 protein than the eutopic endometrial tissue of control subjects (P < 0.05). The findings suggest that the higher frequency of IL-17-producing cells in the PBMCs and endometrial tissues of patients with endometriosis contributes to the pathogenesis of endometriosis.