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关键词： Ancestral haplotypes   HLA   Hematopoietic cell transplant   Non-classical MHC   Polymorphic frozen blocks   Relapse  

摘要： INTRODUCTION:Donors for patients requiring hematopoietic cell transplant (HCT) are selected based on matching genetic sequences encoding the antigen recognition domain of specific HLA loci. However, differences in transplant outcomes in fully matched unrelated HCT compared with sibling HCT suggest that other genetic regions within the major histocompatibility complex (MHC) may contribute to HCT outcomes. METHODS:We sequenced the non-classical MHC loci (NCML) HLA-E, -F, -G, -H, MICA and MICB on a well-characterized retrospective cohort of 157 unrelated donor/recipient HCT pairs to determine the extent of MHC mismatching in matched pairs. RESULTS:Mismatches were seen in one or more NCML in 131 of the 157 pairs (83 %), including 44 of 60 pairs (73 %) that were matched at 4th field resolution for HLA-A, HLA-C and HLA-B and 3rd field resolution for HLA-DRB1, HLA-DRB3,4,5, HLA-DQA1 and HLA-DQB1. Though not statistically significant, transplant outcome analysis suggested that highly HLA matched/NCML matched recipients had a greater risk of disease relapse and reduced likelihood of progression-free survival than recipients that were highly HLA matched/NCML mismatched. CONCLUSION:NCML mismatching is present in HLA-matched unrelated HCT donor and recipient pairs and may contribute to outcomes in unrelated HLA-matched HCT.

关键词： Triple negative breast cancer   IL6   Cancer-associated fibroblast   NF-kappa B   (Willd.) RJWang  

摘要： Ethnopharmacological relevance: The treatment options for triple-negative breast cancer (TNBC) are limited. Traditional Chinese Medicine (TCM) plays an important role in the treatment of TNBC. The herb pair Scutellaria barbata *** and Scleromitrion diffusum (Willd.) *** (SH) is commonly used in clinical practice for its antitumor properties. It has been proven to have good therapeutic effects on tumor-related diseases, but the underlying molecular mechanisms are not yet fully explained. Aim of study: Through bioinformatics, it was validated that IL6, primarily derived from cancer-associated fibroblasts (CAFs), is associated with poor prognosis. Additionally, cell and animal experiments confirmed that SH inhibits tumor proliferation, migration, and growth in an orthotopic tumor model by suppressing the IL6/NF-kappa B pathway. Materials and methods: GEO, TCGA and HPA databases were used to analyze the prognostic value of CAFs and IL6, then IL6 resource was detected. After the bioinformatics, the influence of CAFs and CAFs-derived IL6 on TNBC was verified by experiments both in vitro and in vivo. Cell clone formation assay, wound-Healing assay, and Transwell assay were used to detect the promotion of CAFs and CAFs-derived IL6 and the inhibition of SH in vitro. TNBC model in mice was used to prove the promotion of CAFs and CAFs-derived IL6 and the inhibition of SH in vivo. The biological pathway of NF-kappa B was explored by western blotting through detecting unique molecules. Results: Bioinformatics analysis revealed that higher proportion of CAFs and elevated level of IL6 were significantly associated with poor prognosis in TNBC. At the same time, IL6 was proved predominantly derived from CAFs. After the indication of bioinformatics, experiments in vitro demonstrated that both CAFs and IL6 could enhance the clone formation and migration ability of MDA-MD-231 cells (231), furthermore, the promotion of CAFs was related with the level of IL6. Based on these data,

摘要： Tumors utilize various mechanisms of HLA disruption in order to evade immune surveillance. Previous computational tools have interrogated specific aspects of this process, yet a holistic picture of HLA loss of heterozygosity (LOH), transcriptomic suppression, and alternative splicing has remained challenging. In a recent Nature Genetics study, Puttick and colleagues introduced MHC Hammer, a robust computational toolkit designed to dissect the complexities of HLA disruptions that mediate immune evasion in cancer. By analyzing comprehensive genomic and transcriptomic data across several large cancer cohorts, the study highlights the prevalence of HLA disruptions-particularly alternative splicing events-across various tumor types and identifies HLA LOH as an important immune evasion mechanism during metastasis in lung adenocarcinoma.

关键词： 西施舌   低盐胁迫   存活   酶活性  

摘要： 【背景】西施舌（Coelomactra antiquata）是一种食药兼备的海水经济贝类。近年来，广东省湛江沿海西施舌人工繁育取得成功，并在其近岸海区进行大规模增殖放流。夏季，湛江沿海大量降水造成近岸海水盐度大幅度降低，对西施舌成贝的生长繁殖构成极大的威胁。【目的】考察西施舌的低盐耐受性及免疫相关酶活性的变化。【方法】以产自湛江徐闻海域的西施舌为实验材料，设置盐度缓降组和盐度骤降组，通过比较盐度缓降过程中半数西施舌存活时的临界盐度（50%CSMin）和盐度骤降过程中的72 h西施舌半数死亡时的盐度(72 h LS50)进行探究。取盐度骤降组在0、3、6、12、24、48 h的西施舌鳃组织，利用 酶联免疫吸附试验（ELISA）法考察低盐胁迫下鳃组织的Na+/K+-ATP酶（NKA）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、碱性磷酸酶（AKP）、酸性磷酸酶（ACP）和溶菌酶（LZM）等的酶活性。【结果】在盐度缓降过程中，西施舌的最低存活盐度（SSMin）为18.22，最低临界盐度（CSMin）为10.18，50%CSMin为 13.07。在盐度骤降过程中，72 h LS50为16.86。盐度骤降胁迫48 h对西施舌鳃组织的NKA、CAT、SOD、AKP、ACP和LZM均产生显著影响（P<0.05），其中CAT、SOD、ACP、AKP、LZM酶活性均呈现先上升后下降的趋势，其最大值分别为75.36 U/mL、293.8 U/mL、0.292 U/L、0.321 U/L和5.283 U/mL；NKA酶活性呈现上升趋势，且48 h内的最大值为0.339 U/mL。【结论】在同一盐度下，盐度缓降组的存活率显著高于盐度骤降组。本研究结果旨在为西施舌低盐抗氧化机制分析提供理论支撑，同时对西施舌人工养殖具有重要的指导意义。

关键词： Nanostructured lipid carriers   Cell uptake   Osteoarthritis   Intra-articular administration   Macrophages polarization  

摘要： Macrophages are the main cells present in the synovial membrane. They play an important role in the development and progression of osteoarthritis (OA). After the establishment of the disease macrophages mostly adopt a pro-inflammatory secretory phenotype (OA phenotype) further inducing cartilage degradation. Indomethacin (IND) is a non-steroidal anti-inflammatory drug (NSAID) able to inhibit the synthesis of prostaglandins mediated by both cyclooxygenase isoforms depicting a potent anti-inflammatory capacity. However, the lack of specificity and short half-like of free drugs within the joint cavity limits its utility in controlling inflammation after intraarticular administration. This study aims at developing IND loaded glycosylated nanostructured lipid carriers (NLCs) to selectively target macrophages and promote their reprogramming to an anti-inflammatory phenotype. This approach focused on the local administration of the NLCs, offers a promising therapeutic strategy for treating OA by modulating the inflammatory environment within the joint. NLCs will be designed by combining experimental and in silico docking analyses, and thoroughly characterized to obtain drug delivery systems with high stability and suitable physicochemical properties. The proposed mannose-functionalized systems exhibited adequate particle sizes (approximate to 70 nm) and positive surface charges (> 20 mV) to be efficiently retained in the joint cavity. Moreover, the developed NLCs demonstrated effective and specific uptake by OA-like macrophages leading to a significant decrease in the secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF-alpha similarly to the free drug. Therefore, these systems effectively reprogrammed OA-associated macrophages to adopt a more regenerative phenotype, offering a promising strategy for managing inflammation in OA.

关键词： epitope specificity   HLA genotyping   immunoinformatics   deep learning   transfer learning  

摘要： Accurate prediction of binding between human leukocyte antigen (HLA) class I molecules and antigenic peptide segments is a challenging task and a key bottleneck in personalized immunotherapy for cancer. Although existing prediction tools have demonstrated significant results using established datasets, most can only predict the binding affinity of antigenic peptides to HLA and do not enable the immunogenic interpretation of new antigenic epitopes. This limitation results from the training data for the computational models relying heavily on a large amount of peptide-HLA (pHLA) eluting ligand data, in which most of the candidate epitopes lack immunogenicity. Here, we propose an adaptive immunogenicity prediction model, named MHLAPre, which is trained on the large-scale MS-derived HLA I eluted ligandome (mostly presented by epitopes) that are immunogenic. Allele-specific and pan-allelic prediction models are also provided for endogenous peptide presentation. Using a meta-learning strategy, MHLAPre rapidly assessed HLA class I peptide affinities across the whole pHLA pairs and accurately identified tumor-associated endogenous antigens. During the process of adaptive immune response of T-cells, pHLA-specific binding in the antigen presentation is only a pre-task for CD8+ T-cell recognition. The key factor in activating the immune response is the interaction between pHLA complexes and T-cell receptors (TCRs). Therefore, we performed transfer learning on the pHLA model using the pHLA-TCR dataset. In pHLA binding task, MHLAPre demonstrated significant improvement in identifying neoepitope immunogenicity compared with five state-of-the-art models, proving its effectiveness and robustness. After transfer learning of the pHLA-TCR data, MHLAPre also exhibited relatively superior performance in revealing the mechanism of immunotherapy. MHLAPre is a powerful tool to identify neoepitopes that can interact with TCR and induce immune responses. We believe that the proposed method w

关键词： spondyloarthritis (including psoriatic arthritis)   precision medicine   immunology   cytokines   innate lymphocyte   macrophages  

摘要： Background The phosphodiesterase 4 (PDE4) inhibitor apremilast downregulates the production of IL-23 and other pro-inflammatory cytokines involved in the pathogenesis of psoriatic arthritis (PsA). Aim To investigate the effects of apremilast on the production of cytokines by peripheral blood monocyte-derived macrophages, innate-like lymphocyte cells (ILCs), mucosal-associated invariant T (MAIT) cells, gamma delta T cells, natural killer (NK) cells, and NKT-like cells from patients with PsA manifesting different clinical responses to the treatment. Methods Peripheral blood samples were obtained from patients with PsA at baseline and after 1 and 4 months of apremilast therapy (n = 23) and 20 controls with osteoarthritis. Cytokine expression in peripheral blood monocyte-derived macrophages and ILCs/MAIT/gamma delta T/NK/NKT-like cells was tested by RT-PCR and FACS analyses, respectively;cytokine levels in culture supernatants and sera were analyzed by ELISA. Results PsA monocyte-derived macrophages exhibited higher expressions of IL-23, IL-1 beta, and TNF-alpha, compared with OA controls, more profoundly in patients responding to apremilast. There were 17/23 (74%) PsA patients who were classified as responders to apremilast at 4 months, and a baseline serum IL-23 >1.4 pg/mL was associated with the responder status (AUCROC 0.79;sensitivity 100%, specificity 68%). Of note, apremilast led to a significantly reduced expression of IL-23 in peripheral blood monocyte-derived macrophages;IL-17 in ILC1 and in T cells of responder patients;IFN-gamma in gamma delta T lymphocytes. Conclusion An enhanced myeloid inflammatory signature characterizes PsA monocyte-derived macrophages, and serum IL-23 levels represent candidate biomarkers for PsA response to apremilast.

关键词： interleukin-12   tumor microenvironment   FcRn   SPARC   immunomodulation   fully human albumin binding (FHAB) domain   interferon gamma   immunotherapy  

摘要： Background Cytokines have been promising cancer immunotherapeutics for decades, yet only two are licensed to date. Interleukin-12 (IL-12) is a potent regulator of cell-mediated immunity that activates NK cells and interferon-gamma (IFN gamma) production. It plays a central role in multiple pathways that can enhance cancer cell death and modify the tumor microenvironment (TME). Attempts to dose rIL-12 were initially successful but IFN gamma toxicity in Phase 2 complicated further development in the late 1990s. Since then, better dosing strategies have been developed, but none have achieved the level of cancer control seen in preclinical models. We set out to develop a novel strategy to deliver fully functional IL-12 and other biologics to the TME by binding albumin, taking advantage of its ability to be concentrated and retained in the *** Single-chain variable fragments (scFv) were identified from a human phage display library that bound human, mouse, and cynomolgus macaque serum albumin, both at physiologic and acidic conditions. These were taken through a series of steps to identify strongly binding molecules that don't interfere with the normal physiology of albumin to bind FcRn, giving it prolonged half-life in serum, along with SPARC/GP60, which allows albumin to target the TME. A final molecule was chosen and a single mutation was made that minimizes the potential for immunogenicity. This fully human albumin-binding (FHAB (R)) domain was characterized and manufacturing processes were developed to bring the first drug candidate into the *** Once identified, the murine form of mIL12-FHAB was studied preclinically to understand its mechanism of action and biodistribution. It was found to be much more efficient at blocking tumor growth compared to murine IL-12, while stimulating significant IFN gamma production with minimal toxicity. SON-1010, which uses the human IL-12 sequence, passed through all of the characterization and required toxicolo

关键词： 非小细胞肺癌   免疫检查点抑制剂   放射召回性肺炎   CD8   IL-6  

摘要： 目的 探讨不可切除的IIIB/C和IV期巩固性放疗的非小细胞肺癌（Non-small cell lung cancer ，NSCLC）患者在接受免疫检查点抑制剂（Immune checkpoint Inhibitors，ICI）治疗后，能够触发患者并发放射召回性肺炎（Radiation recall pneumonitis，RRP）的预测指标。方法 回顾性分析青岛市市立医院2020年3月至2023年11月间放疗后序贯ICI治疗的不可切除IIIB/C和IV期巩固性放疗的NSCLC患者，分为RRP组和非RRP组。收集患者临床信息，包括性别、年龄、体质量指数、体能状态评分、TNM分期、平均肺剂量（mean lung dose，MLD）、V20、血压、FEV1、FVC、FEV1/FVC 、PaO2、PaCO2、降钙素原、白细胞介素6（interleukin，IL-6）、外周血CD4+及CD8+T细胞计数，以Logistic回归分析与ROC特征分析结果评估危险因素。结果 此研究共收集到患者55例，包括非RRP组30例（54.45%）、RRP组25例（45.45%），其中RRP危重症3例（3/55，5.45%）。两组的性别、年龄、体质量指数、体能状态评分、TNM 分期、MLD、V20、血压、FEV1、FVC、FEV1/FVC、PaCO2、降钙素原、CD4+细胞均差异无统计学意义（P>0.05）。RRP组PaO2（P =0.007）和CD8+T细胞计数（P=0.040）低于非RRP组，IL-6 浓度（P <0.001）高于非RRP组。PaO2和IL-6在单因素和多因素分析中都显示出较高的显著性（P <0.01），CD8+T细胞在多因素分析中的为较显著因素（P<0.05），ROC曲线AUC值PaO2＞IL-6＞CD8+T细胞。结论 不可切除的IIIB/C和IV期NSCLC患者放疗后序贯ICI治疗，RRP发生率高，但RRP危重症发生率低。PaO2低、IL-6高水平和外周血CD8+T细胞计数减少可作为ICI 触发RRP的高风险因素，具有较准确的预测能力。