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关键词： Major histocompatibility complex - MHC   T cell Receptor - TCR   Adoptive cell therapy - ACT   Human leukocyte antigen - HLA   Genetic  

摘要： Understanding regional distribution of HLA frequencies is crucial for optimizing enrollment in HLA-restricted clinical trials and to promote trial diversity per the Food and Drug Administration's 2020 mandate. Using US HLA frequency data and census demographics we developed a method to create high-resolution HLA class 1 genotypic frequency maps. Analyzing HLA-A*11:01 and HLA-B*58:01 as alleles of interest, we found significant US regional variations. HLA-A*11:01, which presents KRAS neoantigen mutations targeted by TCR T-cell therapies, showed 10-15% genotypic frequency (national average 11.2%), with western US states 1.5 times higher than average and local variations within California (10-19%). These insights can be used to guide clinical trial site selection, for example, in National Cancer Institute (NCI) cancer center catchment areas. For HLA-B*58:01, which reacts pharmacogenetically with allopurinol and results in severe cutaneous adverse reactions, Mississippi had a high frequency among US states, which could be used to guide potential public safety campaigns. This method can identify regions with high HLA type representation, aiding efficient patient identification and enrollment for HLA-specific clinical trials and health-awareness efforts.

关键词： Triple-negative breast cancer   RNA sequencing   Mast cell   CD52   IL-6/JAK/STAT3  

摘要： The aggressive nature and rapid progression of triple-negative breast cancer (TNBC), coupled with a high likelihood of recurrence and mortality, underscore the critical need for effective treatments. While immunotherapy presents promising advantages for those with triple-negative breast cancer (TNBC), its efficacy is not universal. This disparity highlights the importance of investigating survival outcomes and prognostic factors for those TNBC patients who don't respond well to immunotherapy. Our study leverages both bulk and single-cell RNA sequencing data to conduct an in-depth analysis, revealing that genes associated with mast cells (PCMT1, VDAC1, YWHAB, BRD4, BTG1, and CD52) are pivotal in prognostication for TNBC patients. Laboratory experiments have further substantiated our findings, demonstrating that the overexpression of CD52 in mast cells impedes the proliferation, invasion, and metastasis of breast cancer cells. Further anti-CD52 treatment inhibiting breast tumor growth in vivo. Additionally, we have discovered that CD52 elicits its antitumor effects by meditating the IL-6/JAK/STAT3 signaling pathway. These insights not only enhance the prognostic significance of mast cells in TNBC but also pave the way for the development of novel targeted immunotherapy strategies.

摘要： Innovations in biologics are transforming the treatment of psoriatic diseases. The ability to target specific levels of immune activation provides a distinct advantage. Interleukin (IL)-17 inhibitors fall into this class of biologics, and they are effectively used to treat a spectrum of psoriatic diseases, such as psoriasis vulgaris and psoriatic arthritis. In recent years, anti-IL-17 agents have been the focus of therapeutic development, with various formulations and routes of administration. In this manuscript, we review pipeline anti-IL-17 therapies for psoriatic diseases identified through a search of *** (January 2019-December 2024) and other databases. Key agents under investigation include netakimab, vunakizumab, xeligekimab, gumokimab, HB0017, CJM 112, JS005, 608, LZM012, ZL-1102, izokibep, sonelokimab, DC-806, DC-853, and LEO 153339. Both preclinical and clinical trial data for each agent are summarized, with an emphasis on their efficacy, adverse effects, immunogenicity, and future outlooks.

关键词： cGAS/STING signalling pathway   CTLA4-Ig   obliterative bronchiolitis   type I interferon  

摘要： BackgroundOur previous findings have underscored the role of innate immunity in obliterative bronchiolitis (OB). However, despite the central importance of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signalling pathway in innate immune responses, its specific contribution to OB progression remains largely *** murine orthotopic tracheal transplantation model was established to replicate OB pathogenesis. RNA sequencing and single-cell RNA sequencing data were analysed to investigate mechanisms underlying OB. Key molecules of the cGAS/STING pathway were assessed using immunofluorescence staining. Macrophage-specific Sting1 knockout mice were generated to investigate the role of the cGAS/STING pathway in OB. Haematoxylin and eosin staining and Masson's trichrome staining were utilised to evaluate allograft stenosis and fibrosis. Immune cell infiltration and cytokine expression were analysed using immunofluorescence staining and qRT-PCR. Flow cytometry was used to characterise splenic T-cell subsets and assess co-stimulatory molecule expression in *** cGAS/STING pathway was upregulated in macrophages infiltrating allografts. Macrophage-specific Sting1 knockout significantly attenuated alloreactive T-cell responses and alleviated OB. Furthermore, Sting1 deletion reduced the expression of inflammatory marker NOS2, antigen-presenting molecule MHC class II and co-stimulatory molecules (CD80 and CD86) in macrophages. Mechanistically, Sting1 knockout inhibited the production of interferon-alpha 2 (IFN-alpha 2), while the protective effect of macrophage-specific Sting knockout was reversed by IFN-alpha 2 administration. Importantly, STING inhibition enhanced the allograft tolerance-promoting effects of cytotoxic T-lymphocyte-associated antigen 4-Ig (CTLA4-Ig), leading to the preservation of the airway *** study demonstrated that cGAS/STING signalling pathway exacerbated allograft rejection in

关键词： dialysis initiation   free IL-18   infection   multicenter prospective cohort study  

摘要： Background. Compared to the general population, individuals who are undergoing hemodialysis are at a higher risk of contracting severe infectious diseases, and their mortality rate from infectious diseases is also higher. We investigated the serum free interleukin-18 [free state of interleukin-18 (IL-18)] concentration as a prognostic factor for hemodialysis patients' infection risk. Methods. The Ibaraki Dialysis Initiation Cohort (iDIC) study is a multicenter prospective cohort investigation of patients undergoing a new initiation of dialysis in a local region of Japan. We performed a survival analysis of several events requiring hospitalization and compared the Kaplan-Meier curves of the "low" and "high" serum free IL-18 concentration groups. To adjust for confounding factors, we also performed a Cox proportional hazards analysis. Results. We analyzed the serum free IL-18 concentration of samples from 295 patients randomly selected from the blood sample bank of the iDIC study. The mean free IL-18 concentration was 8.7 +/- 5.3 pmol/l. The cumulative incidence of infectious events was significantly higher in the low free IL-18 group (<6.0 pmol/l, log-rank test P < .01). The Cox proportional hazards analysis revealed that low serum free IL-18 (<6.0 pmol/l) was an independent factor associated with the development of infectious events. Total IL-18 and IL-18BP (binding protein) showed no association with infectious events. Conclusion. A low serum free IL-18 concentration in the dialysis initiation period is a potential marker for predicting the development of severe infection in these patients.

关键词： trifunctional   antibody-cytokine fusion proteins   common gamma chain receptor family   IL-15   IL-7   IL-21   cancer immunotherapy  

摘要： Cytokines from the common gamma chain receptor family, such as IL-15, IL-21 and IL-7, show promise for cancer immunotherapy and have been incorporated individually into the immunocytokine approach. However, their efficacy as monotherapy is limited. Here, we investigated the molecular design of tumor-directed trifunctional antibody-cytokine fusion proteins for a combinatorial approach of IL-15 with either IL-7 or IL-21. Various fusion proteins differing in antibody format, cytokine composition and arrangement were generated and cooperative cytokine activity assessed in solution and bound to target cells. Comparative analysis revealed that formats with cytokines positioned at the N- and C-termini of the antibody were more effective than those arranged in series. For the former design, cooperative effects were observed with the scFv-based (IL-15+IL-7) trifunctional fusion protein, primarily enhancing the proliferation of naive T cells, while the scFv/Fab-based (IL-15+IL-21) trifunctional fusion proteins enhanced IFN-y release and the cytotoxic potential of T cells. Combining cytokines in the two-in-one molecule approach was principally advantageous when bound to target cells. Greater potency in inducing JAK-STAT pathway activation highlighted the importance of cytokine colocalization for cooperative receptor activation. Compared to the Fab-based (IL-15+IL-21) format, the scFv-based (IL-15+IL-21) format displayed a tendency towards higher activity in targeted and lower activity in untargeted settings, emphasizing the targeted concept. Thus, this study underscores the importance of molecular design in developing trifunctional immunocytokines and identified the scFv-based trifunctional (IL-15+IL-21) fusion protein, with the antibody in the central position, as a particularly promising candidate for further drug development.

关键词： Hypoxia-inducible factor-1 alpha (HIF-1 alpha)   Interleukin-6   Acute aortic dissection  

摘要： Background Studies have reported that Acute Stanford type A aortic dissection (ATAAD) is associated with hypoxia and inflammation. This study aims to explore the levels of HIF-1 alpha and IL-6 in the serum of patients with ATAAD, and to analyze the association between these two factors as well as their potential clinical significance. Methods Serum samples were collected from 82 ATAAD patients and 19 healthy controls. Subsequently, the levels of HIF-1 alpha and IL-6 in the serum of these samples were measured using the enzyme-linked immunosorbent assay (ELISA). Results The results showed that the serum HIF-1 alpha level in patients with ATAAD were significantly reduced compared with the healthy control group [10.72 (7.28,14.92) vs. 19.54 +/- 8.07 pg/mL, p < 0.0001], and the serum IL-6 level were significantly increased [3.12 (1.97, 9.13) vs. 1.13 (0.98, 1.42) pg/mL, p < 0.0001]. Moreover, there was no statistical difference of HIF-1 alpha level in ATAAD patients with or without hypoxemia and IL-6. However, there was a significant positive correlation between the levels of IL-6 and the expression of HIF-1 alpha (r = 0.5435, P < 0.0001). Conclusion We found that levels of HIF-1 alpha and IL-6 were abnormal in patients with ATAAD. Moreover, the HIF-1 alpha and IL-6 level in ATAAD patients were positively correlated, suggesting that HIF-1 alpha and IL-6 may play roles simultaneously during the development of acute aortic dissection.

关键词： HPV感染   HLA多态性   HPV16 E6突变   T细胞抗原表位  

摘要： 目的:研究新疆地区维、汉族宫颈癌妇女在不同遗传背景下HLA的多态性,分析HPV16 E6突变对T细胞抗原表位的影响,预测HLA分子与T细胞抗原表位的亲和力。方法:收集2017年至2020年于新疆维吾尔自治区人民医院妇科就诊的HPV16阳性宫颈鳞状细胞癌维吾尔族、汉族患者共52例,获取患者的血液及组织样本;通过高通量测序技术对其进行HLA分型分析,比较各等位基因在两民族中的分布频率;运用IEDB数据库对本研究团队前期研究中所获得的维吾尔族宫颈癌患者的HPV16 E6突变基因进行抗原表位预测及相关分析处理得到其候选表位,再利用NetMHCIIpan 4.0 Server与NetMHCpan 4.0 Server在线软件预测该抗原表位与HLA分子的亲和力变化。结果:新疆地区维、汉族宫颈癌患者之间存在显著差异的HLA基因型共有11个;HPV16 E6突变基因主要与14个T细胞抗原表位的变异有关;HPV16 E6突变导致的T细胞抗原表位112761、112929与HLA分子亲和力显著增强;HPV16 E6突变导致的T细胞抗原表位110846与HLA分子亲和力显著减弱。结论:新疆地区维吾尔族宫颈癌妇女HPV16 E6突变导致的T细胞表位的改变,可能是该人群HPV低感染率、宫颈癌高发率的免疫学原因之一。

关键词： Cholangiocarcinoma (CCA)   carnitine palmitoyltransferase II (CPT2)   NF-kappa B   bioinformatics  

摘要： Background: Carnitine palmitoyltransferase II (CPT2) is an important regulatory enzyme involved in fatty acid oxidation;it is associated with the prognosis and progression of colorectal and ovarian cancers, but its expression and role in cholangiocarcinoma (CCA) have been less explored. This study aims to explore the role and molecular mechanism of CPT2 in CCA and to determine the potential relationship between CPT2 expression and the prognosis of CCA patients. Methods: Bioinformatics analyses were used to assess CPT2 expression in CCA and other cancers. Independent prognostic factors of CCA were identified for univariate and multivariate Cox regression analyses. Nomograms were employed to predict CCA 1-, 3-, and 5-year survival. Kaplan-Meier curves explored the correlation between CPT2 expression and CCA survival. We used time-dependent receiver operating characteristics (ROCs) to evaluate the predictive efficiency of CPT2. Furthermore, potential mechanisms of CPT2 were analyzed by Gene Set Enrichment Analysis (GSEA) in CCA. CPT2 expression in peripheral blood, tissues, and cell lines of CCA was verified by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The effect of CPT2 on CCA cells was gauged using Cell Counting Kit-8 (CCK-8), cell cycle, apoptosis, and transwell assays. Finally, the regulation of the TNF alpha/ NF-kappa B pathway by CPT2 was verified by Western blotting. Results: CPT2 expression was down-regulated in many cancers, including CCA. COX regression analyses showed that CPT2 expression and the clinical stage could be independent prognostic factors in CCA. Nomograms indicated that the lower probability of CCA survival was associated with the lower expression of CPT2 and the higher clinical stage. The Kaplan-Meier curve showed that the low expression of CPT2 was related to a poor prognosis in CCA. The time-dependent ROC curve demonstrated the predictive ability of CPT2 [1-, 3-, 5-year are under the curve (AUC) =0.933,