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关键词： Platelet transfusion refractoriness   anti-HLA antibody   anti-HLA-C autoantibody   hematologic disorders  

摘要： Objectives Platelet transfusion refractoriness (PTR) is a frustrating clinical problem, and primary and persistent (P/P) PTR who experienced persistent PTR since the first transfusion was failed to be well recognized. This study aims to investigate the incidence and risk factors for P/P PTR. Methods Patients with hematologic disorders who underwent HLA high-resolution genotyping and donor-specific HLA antibody or panel reactive antibody (PRA) testing between January 2019 and March 2023 were reviewed. Clinical data including infection history, splenomegaly, frequency and quantity of blood transfusions, and transfusions response were delineated and subsequently analyzed. Results 114 patients were included retrospectively, and 1071 transfusions were recorded. The overall incidence of PTR was 28.95% (33/114), with 63.63% (21/33) being P/P PTR. Anti class I HLA (anti-HLA-I) antibody was identified as an independent risk factor for ineffective platelet transfusion through multivariate logistic regression analysis (p = .034). Interestingly, anti-HLA-C autoantibodies were first found in six patients, and both anti-HLA-A and C autoantibodies were detected in one case, comprising a total of 10.71% (6/56) of HLA-I antibody-positive patients. Further analysis revealed that anti-HLA-C autoantibody was identified as an independent risk factor for P/P PTR (p = .039). Among patients with positive anti-HLA-C antibodies, significant differences in the effectiveness of ABO, D-matched and cross-matching transfusions were observed between patients with or without anti-HLA-C autoantibodies (p < .001 and p = .017). Notably, platelet transfusions independence was achieved by two of the four patients who received rituximab. Conclusions This work emphasized the significance of anti-HLA-C autoantibody for P/P PTR in hematological patients, and rituximab may therapeutic.

关键词： MHC I   immunopeptidome   colorectal cancer   topoisomerase inhibitor   microsatellite  

摘要： Immunotherapy options for microsatellite stable (MSS) colorectal cancer are currently very limited. The lack of detectably unique or altered immunogens in the tumor microenvironment may be a factor. Radiation and chemotherapy may enhance immunotherapy by increasing cancer cell visibility through Major Histocompatibility Complex I (MHC I) expression. To investigate this, we treated MSS and microsatellite-instable (MSI) colon cancer cells with a topoisomerase inhibitor and analyzed MHC I-associated peptides. Treatment increased peptide numbers by 5% in RKO (MSI) cells and 83% in SW620 (MSS) cells, with 40-50% of peptides being exclusive to treatment. Additionally, clustering analysis revealed a set of peptides with uniquely conserved residues displayed only in treated MSS SW620 cells. Gene Ontology analysis of MHC I-displayed proteins revealed a treatment-induced increase in extracellular vesicle- and nuclear-derived proteins, alongside reduced cytosolic protein sampling. Overall, we present evidence for treatment-inducible differential display of peptides, some of which may affect interactions and functions of immune cells. Given the multitude of factors that modulate the effects of increased MHC I expression and associated peptides, further studies are needed to elucidate the pathophysiological implications of these changes.

关键词： IL7R   Ischemia–reperfusion injury   KAS-Seq   Leukocytes   Target  

摘要： Ischemia–reperfusion injury (IRI) is one of the leading causes of mortality and disability worldwide. Owing to its complex pathogenesis, there is still a lack of effective therapeutic targets in clinical practice, and exploring the mechanism and targets of IRI is still a major clinical challenge. This study aimed to explore the genetic alterations in leukocytes in peripheral blood after ischemia–reperfusion, aiming to discover new biomarkers and potential therapeutic targets. KAS-Seq (Kethoxal-assisted single-strand DNA sequencing) was used to obtain gene expression profiles of circulating leukocytes in a porcine ischemia–reperfusion model at 24, 48, and 72 h post-ischemia‒reperfusion. This method integrated genes that exhibited regular changes over time. In this study, we thoroughly analyzed the dynamic changes in gene expression post-IRI, revealing significant enrichment in key signaling pathways that regulate immune responses and T-cell activation over time. Our identification of the interleukin-7 receptor (IL7R) was particularly striking, as it plays a crucial molecular role in IRI. Additionally, using database mining technology, we confirmed the close relationship between IL7R and IRI, explored the interaction between interferon-γ (IFNG) and IL7R in T-cell activation, and clarified their joint influence on ischemia–reperfusion injury. Using KAS-Seq analysis of leukocytes from peripheral blood, we successfully delineated the temporal patterns of gene expression and changes in signal transduction pathways in porcine models of ischemia–reperfusion. Subsequent in-depth analysis identified IL7R as a potential novel therapeutic target for IRI. The pivotal role of this gene in modulating immune responses provides innovative avenues for the development of IRI treatments. © The Author(s) 2025.

摘要： The Interleukin-36 (IL-36) cytokine family have emerged as important players in mounting an inflammatory response at epithelial barriers and tailoring appropriate adaptive immune responses. As members of the Interleukin-1 superfamily, IL-36 cytokines lack a signal peptide for conventional secretion and require extracellular proteolysis to generate bioactive cytokines. Although the IL-36 family plays an important role in the pathogenesis of plaque and pustular psoriasis, little is known about the release mechanisms of these cytokines from keratinocytes and the physiological stimuli involved. Nucleic acid released from damaged or dying keratinocytes initiates early inflammatory signals that result in the breaking of tolerance associated with psoriasis pathogenesis onset. Cathelicidin peptide, LL37 binds to DNA or double-stranded RNA (dsRNA) and activates a type I Interferon responses in plasmacytoid dendritic cells and keratinocytes. Here, we demonstrate that LL37 binds to dsRNA and induces IL-36γ release from human primary keratinocytes. LL37/dsRNA complexes activate RIG-I-like Receptor signalling, resulting in Caspase-3 and Gasdermin E (GSDME) cleavage. Subsequent GSDME pore formation facilitates IL-36γ release. This response is magnified by priming with psoriasis-associated cytokines, IL-17A and IFNγ. IL-36γ release in this manner is largely independent of cell death in primary keratinocytes and lacked extracellular proteolysis of IL-36γ. Conversely, transfection of keratinocytes directly with dsRNA synthetic analogue, Poly(I:C) induces NLRP1 inflammasome activation, which facilitates IL-36γ expression and release in a GSDMD-dependent manner. Inflammasome-associated cell death also enables extracellular processing of IL-36γ by the release of keratinocyte-derived proteases. These data highlight the distinct responses triggered by dsRNA sensors in keratinocytes. Depending on the inflammatory context and magnitude of the exogenous threat, keratinocytes will release IL

摘要： To elucidate the relationship between circulating cytokines and the prognosis of microsatellite-stable(MSS) colorectal cancer (CRC) patients, we examined the correlation between circulating cytokine levels and tumor immune infiltration microenvironment in this patient population. By conducting a preliminary analysis of the GEO database, we identified five core genes associated with colorectal cancer and further analyzed their impact on immune infiltration. We measured serum cytokine levels and validated the immune infiltration results through immunohistochemical staining of common inflammatory cell markers, including CD3, CD4, CD8, CD163, and FOXP3. Our findings indicate that serum cytokine levels significantly influence immune infiltration in colorectal cancer, particularly IL6 and IFNγ, which play crucial roles. Specifically, the infiltration of M2-type macrophages and CD8 + T cells is correlated with serum levels of IL6 and IFNγ. MSS CRC patients with elevated IL6 expression exhibit improved prognosis. © The Author(s) 2025.

关键词： CDC42   Cutaneous melanoma   IL-6   Tetrandrine  

摘要： Background: Cutaneous melanoma (CM) is a skin melanocytes-derived malignant tumor accounting for most of the death in skin cancers. The clinical drug for CM is limited or with poor efficacy. Tetrandrine is a natural alkaloid with diverse pharmacological effects including anti-cancer. This study investigated the anti-cancer potential and mechanisms of tetrandrine in CM, which might provide more therapeutic options for CM. Methods: The effects of tetrandrine on CM cell proliferation were evaluated via CCK8 and colony formation assay. The cell cycle analysis was conducted by flow cytometry. qRT-PCR and western blotting were performed to determine relevant RNA and protein levels. Co-Immunoprecipitation assay was used to detect the protein-protein interaction. Small interfering RNA transfection or lentiviral transduction were used to knockdown or overexpress target proteins, respectively. Results: Tetrandrine triggered a significant G0/G1 cell cycle arrest in A375 and SK-MEL-2 cells. Tetrandrine decreased the expression of the cell cycle activator cyclin D1 and increased cell cycle inhibitor p21. In-depth study revealed that the anti-CM activities of tetrandrine mainly dependent on Interleukin-6 (IL-6) and cell division cycle 42 (CDC42) regulation. A direct interaction between IL-6 and CDC42 was identified. Tetrandrine suppressed IL-6 expression and subsequently inhibited CDC42, which in turns lead to G0/G1 cell cycle arrest in CM cells. Conclusion: Tetrandrine suppressed CM cell growth by triggering G0/G1 cell cycle arrest via IL-6/CDC42 inhibition. Tetrandrine should be a promising compound for CM treatment. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025.

关键词： Hepatitis B virus   LY6E   Peg-IFN-α   TRIM6  

摘要： Background: Pegylated interferon alpha (Peg-IFN-α) has the potential to eradicate hepatitis B surface antigen (HBsAg). This study aimed to investigate whether the expression levels of lymphocyte antigen 6 family member E (LY6E) and tripartite motif-containing protein 6 (TRIM6) mRNAs in peripheral blood mononuclear cells (PBMCs) of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) patients is associated with the response to Peg-IFN-α treatment and HBsAg clearance. Methods: In this prospective study, HBeAg-negative chronic HBV patients treated with Peg-IFN-α were followed for 48 weeks. The participants were classified into two groups, the virological response (VR) group and nonvirological response (NVR) group, according to the changes in HBV DNA and HBsAg levels observed at week 48 of treatment. Furthermore, these patients were divided into a serological response (SR) group and a nonserological response (NSR) group, depending on whether they exhibited a loss of serum HBsAg or evidence of seroconversion. The expression levels of LY6E and TRIM6 mRNAs in PBMCs were evaluated using real-time quantitative PCR with fluorescence detection. The diagnostic performance of LY6E and TRIM6 was assessed by analyzing the receiver operating characteristic (ROC) curve and calculating the area under the ROC curve (AUC). Results: After the treatment period, the observed VR and SR rates were 44.64% and 28.57%, respectively. Dynamic changes in LY6E and TRIM6 mRNA levels were significantly different between the VR and NVR groups and between the SR and NSR groups. Multivariate analysis revealed that TRIM6 was independently associated with VR at weeks 12 and 24 of Peg-IFN-α therapy and with SR at week 12;in addition, LY6E was independently associated with VR at week 12 and SR at week 24. At week 24, the area under the curve (AUC) for LY6E in the prediction of VR was 0.6942, and the AUC for the prediction of SR was 0.7766;at week 12, TRIM6 had AUCs of 0.7600 for the predi

摘要： Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, often caused by sarcomere gene mutations, though many sporadic cases remain genetically unexplained. Here we show that the somatic variant NAP1L1 p.D349E was involved in cardiac hypertrophy in sporadic HCM patients. Through next generation sequencing, we found that somatic variant NAP1L1 p.D349E was recurrent in the cardiomyocytes of gene-elusive sporadic HCM patients. Subsequent in vivo and in vitro functional analysis confirmed that NAP1L1 p.D349E contributes to HCM by triggering an innate immunity response. This mutation destabilizes nucleosome formation, causing DNA to leak into the cytoplasm. This leakage activates a key immune pathway, cGAS-STING, which leads to the release of inflammatory molecules and promotes heart muscle thickening. Our findings reveal a new mechanism driving HCM and suggest that somatic variants could be important in understanding and management of HCM. © The Author(s) 2025.

关键词： 造血干细胞   造血干细胞移植   造血干细胞动员   细胞因子   血小板生成素   CXCR4拮抗剂   整合素拮抗剂   化疗   动员效能  

摘要： 背景:造血干细胞移植是一种广泛应用于血液系统恶性和非恶性疾病的重要治疗手段,动员和收集足够的造血干细胞是保证患者移植后快速、持续造血功能重建的前提,但最常用的粒细胞集落刺激因子联合或不联合化疗的经典方案仍有10%-40%的动员失败率。目的:综述近年来造血干细胞动员现状,分析不同方案的优缺点,展望未来动员新方案。方法:以“造血干细胞,造血干细胞移植,造血干细胞动员,细胞因子,血小板生成素,CXCR4拮抗剂,整合素拮抗剂,化疗,动员效能”为中文关键词,以“hematopoietic stem cell,hematopoietic stem cell transplantation,hematopoietic stem cell mobilization,cytokines,thrombopoietin,CXCR4 antagonists,integrin antagonist,chemotherapy,mobilization efficiency”为英文关键词,在CNKI、PubMed、万方数据库进行检索,文献语种限制为中文、英文,检索年限为1990-2024年,共检索到300多篇文献,最终纳入68篇文献进行分析。结果与结论:越来越多的研究发现粒细胞集落刺激因子联合普乐沙福、白细胞介素、血小板生成素及整合素拮抗剂等能够更加有效地动员造血干细胞,联合使用可以减少粒细胞集落刺激因子的使用剂量,减少相关不良反应。一些新药如可溶性重组flt3-配体(简称CDX-301)、双重α9β1/α4β1整合素抑制剂BOP等可与粒细胞集落刺激因子联合,促进造血干细胞动员。此外还发现一些潜在的动员靶点如前列腺素E2受体及1-磷酸鞘氨醇等,尚在研究阶段。除固有的患者特征、治疗特征外,开发纳入生物标志物的预测模型,有助于有效预测造血干细胞动员失败,提升干细胞动员技术。

关键词： Peptides   Artificial neural networks   HLA-I alleles   IFN-gamma   CD107a  

摘要： Toxoplasma gondii infects approximately 30% of the population, and there is currently no approved vaccine. Identifying immunogenic peptides with high affinity to different HLA molecules is a promising vaccine strategy. This study used an in silico approach using artificial neural networks to identify T. gondii peptides restricted to HLA-A*02, HLA-A*24, and HLA-B*35 alleles. Proteomes from seven T. gondii strains and transcriptomic data of overexpressed genes from T. gondii-RH in human PBMC were also used. Parasite protein sequences were analyzed with R 'Epitope Prediction' library. Peptide candidates were evaluated in the artificial neural networks based on the probabilities of output neurons (p > 0.5). The IFN-gamma responses in PBMC from T. gondii seronegative and seropositive individuals were evaluated by ELISpot. Peptides with higher IFN-gamma induction were evaluated to identify cytotoxic response in CD8+ T cells (CD107a). In silico analysis identified 36 peptides from T. gondii proteins with predicted affinity to HLA-A*02, A*24, and B*35 alleles. Experiments with PBMCs revealed that a peptide restricted to HLA-A02 (P1: FLFAWITYV) induced a significant increase in IFN-gamma-producing cells (p = 0.004). For HLA-A24, a peptide (P8: VFAFAFAFFLI) also induced a significant IFN-gamma response (p = 0.004), while for the HLA-B*35 allele, the P6 peptide (YPIAPSFAM) induced a response that differed significantly from the control (p = 0.05). These peptides induced also a significant percentage of central memory CD8 + T cells expressing the degranulation marker CD107a (p < 0.05). Finally, we identified three T. gondii peptides that induced IFN-gamma response, and a cytotoxic response measured by CD107a expression on CD45RAneg-CD8 cells. These peptides could be considered part of a multi-epitope vaccine against toxoplasmosis in humans.