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关键词： Chiral metal-organic polyhedron   Gas chromatography   Stationary phase   Separation  

摘要： Chiral metal-organic polyhedra (CMOPs) have come to be recognized as ideal materials for chromatographic enantioseparation owing to their unique molecular recognition ability. Herein, the utilization of a novel chiral stationary phase (CSP) based on CMOP-IL ([Cu12(LIL)12(H2O)12], IL = L-isoleucine) for gas chromatographic separation was explored. A variety of mixtures (n-alkanes, n-alcohols and alkylbenzenes) and multiple isomers were effectively separated on the CMOP-IL capillary column. The separation performance of the CMOP-IL column for most mixtures and isomers is superior to that of the previously reported MOP-V ([Cu12(LV)12(H2O)12], V = L-valine) column. Notably, the CMOP-IL capillary column exhibited excellent enantioselectivity towards various racemates that include alcohols, ethers, aldehydes, epoxides, and amino acid derivatives. In comparison with the commercial beta-DEX 120 column, MOP-V column, and Co-L-GG column, the complementary chiral resolving capabilities of the MOP capillary column were demonstrated in separating racemates. Additionally, the relative standard deviation (RSD) values of retention time and peak area of allyl glycidyl ether and o,m,pnitrotoluene stayed within a range below 1 %, indicating good repeatability and stability of the MOP column in gas chromatographic separation. The study indicates that CMOP based on L-isoleucine, as a novel CSP, holds promising applications in gas chromatography.

摘要： Acute myeloid leukemia (AML) patients present with CD8 exhaustion signatures, and pharmacologic inhibition of checkpoints can have therapeutic benefit. The alarmin IL-33 and its receptor STimulation-2 (ST2) promote activation of tissue-regulatory T cells (T_reg cells) and accelerate malignant progression in solid tumors, but their role in leukemia remains unclear. Here, we show that ST2⁺ T_reg cells are enriched in bone marrow (BM) of humans and mice with AML and promote CD8⁺ T cells depletion and exhaustion. ST2 deficiency in T_reg cells restores CD8⁺ T cell function, decreasing AML growth via retention of ST2⁺ T_reg cells precursors in lymph nodes. AML-activated ST2⁺ T_reg cells lack T-bet, IFN-γ and Bcl-6, and kill intratumoral CD8⁺ T cells by amplified granzyme B-mediated cytotoxicity compared to non-AML primed T_reg cells. Engineered anti-ST2 antibodies induce ST2⁺ T_reg cells apoptosis to extend survival in AML models. Together, our findings suggest that ST2 is a potential checkpoint target for AML immunotherapy. © The Author(s) 2025.

关键词： (Alphabetical order): Arthritogenic peptide   Axial Spondyloarthritis   HLA-B27   Neutrophils   Neutrophil Extracellular Trap   New Bone Formation   T Cells  

摘要： Purpose of Review Axial spondyloarthritis (axSpA) is a chronic multi-organ rheumatic disease affecting various tissues, and recent key advancements have provided significant insight into understanding its immunopathology. Recent Findings Expanded CD8(+) T cell subsets bearing unique T cell receptor (TCR) motifs (TRAV21/TRBV9) in HLA-B27-positive axSpA patients or those with acute anterior uveitis were recently identified. These T cells can bind to self- and bacterial-derived peptides, supporting the "arthritogenic peptide" hypothesis. Monoclonal antibody-mediated elimination of these expanded T cells has shown potential as a novel treatment for axSpA in a phase II clinical trial, offering a groundbreaking therapeutic approach. In addition to T cells, neutrophils have emerged as important mediators of both inflammation and new bone formation in axSpA, potentially contributing to HLA-B27-independent immune pathomechanisms. Key neutrophil-derived molecules-such as macrophage migration inhibitory factor, hypoxia-inducible factor 1-alpha, caspase recruitment domain-containing protein 9, and neutrophil extracellular traps (NETs)-have been shown in preclinical models to promote Th17-mediated inflammation and reduce regulatory T cell numbers. These mechanisms may be relevant to axSpA pathogenesis and represent potential new therapeutic targets. Summary In recent years, significant progress has been made in understanding the immunopathology of axSpA through both HLA-B27-dependent and -independent mechanisms. However, key questions remain. The pathogenic HLA-B27:05-bound peptides driving CD8(+) T cell expansion remain unidentified. Moreover, due to the diversity of TCR motifs that recognize self- and microbial peptides, therapies targeting a single TCR (e.g., TRBV9) may have limited efficacy. Further research is needed to clarify axSpA pathogenesis across both pathways.

关键词： Immune response   Inflammation   Fibroblasts   Transcriptome   Tumour necrosis factor-alpha  

摘要： Objective: In this study, we examined the molecular response of human skin fibroblasts to an inflammatory cytokine to evaluate their suitability as models for immunopathology research. Methods: Skin fibroblasts were stimulated with tumour necrosis factor (TNF)-alpha, and the transcriptome was profiled via RNA-Seq. The differentially expressed genes were screened to predict immunological pathways and interactions. The cytokines and signaling pathways were validated at protein level. Similarly to immune cells, TNF-alpha caused transcriptional and transductional changes in fibroblasts. Results: Functional analysis revealed significant enrichment of TNF-alpha signaling and cell chemotaxis (normalized enrichment score = 2.59 and 3.42). We also detected enrichment of nuclear factor kappa B (NF-kappa B) target genes and NF-kB activation, confirmed by complete protein degradation of its inhibitor I kappa Ba (p = 0.0019). The MAPK/ERK and p38 MAPK pathways were also activated. Finally, we observed significant secretion of proinflammatory cytokines and chemokines, such as interleukin 6 (p = 0.02), CXCL8 (p = 0.027), CCL2 (p = 0.028) and CCL5 (p = 0.016). Conclusion: This study advances the biological understanding of skin fibroblast responses to TNF-alpha, revealing their intracellular pathways and secretome. It discloses techniques for leveraging fibroblasts' potential as in vitro models to identify inflammatory drivers, particularly when alternative models are inaccessible.

关键词： anti-IL-6 autoantibody   durvalumab   immune-related adverse event   small-cell lung cancer  

摘要： Durvalumab plus platinum-based chemotherapy is the first-line treatment for extensive-stage small-cell lung cancer. Immune checkpoint inhibitors (durvalumab) can cause immune-related adverse events (irAEs). We herein report the first case of fatal sepsis with anti-interleukin-6 autoantibody production following durvalumab administration. A 62-year-old woman with extensive-stage small-cell lung cancer received carboplatin-etoposide plus durvalumab chemotherapy. Serum C-reactive protein (CRP) levels decreased below the detection sensitivity post-treatment. She developed severe sepsis during maintenance durvalumab therapy;however, her serum CRP level did not increase. The serum tested positive for anti-interleukin-6 autoantibodies, which can cause CRP-less infections. Anti-interleukin-6 autoantibody production and subsequent sepsis without serum CRP elevation are possible irAEs.

关键词： ADA2 deficiency   Beh & ccedil   et's disease   Rheumatic disease   Children   HLA-B*51   Autoinflammatory  

摘要： Purpose Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease resulting from biallelic loss-of-function mutations in ADA2 gene. It has variable clinical manifestations, some of which can mimic Beh & ccedil;et's disease (BD). Herein, we present a family of three siblings diagnosed with DADA2, two of whom were initially misdiagnosed as BD based on clinical phenotype including positive human leukocyte antigen B51 (HLA-B*51). Methods Gene mutational analysis was performed by whole exome (WES) and Sanger sequencing. Results We reported two siblings presented with recurrent oral ulcers, fever, arthritis, and skin lesions, alongside elevated inflammatory markers and HLA-B*51 positivity, leading to an initial misdiagnosis of BD. Genetic testing later revealed a homozygous ADA2 variant (c.139G > A ***47Arg) in both siblings and their asymptomatic younger sister, confirming DADA2 diagnosis. Thereafter, we reviewed the literature to identify other patients misdiagnosed with BD but later found to have DADA2. This resulted in a cohort of 10 DADA2 patients, including our two reported siblings. The median time from symptoms onset to the final diagnosis of DADA2 was 7 years. All patients exhibited BD-like phenotype, except for uveitis, and 8 were HLA-B*51 positive, which likely contributed to the diagnostic confusion. Conclusion These findings highlight the broad clinical spectrum of DADA2, which can resemble BD, and suggest that HLA-B*51 positivity in DADA2 may further complicate diagnosis. Clinicians should maintain a high index of suspicion for DADA2 in early-onset BD-like cases, particularly without uveitis, or a family history of similar symptoms. Further studies are warranted to explore HLA-B*51 role in DADA2 phenotype.

关键词： Maniq people   Hunter-gatherer   HLA diversity   Positive selection   Balancing selection  

摘要： The Maniq, a small and isolated nomadic hunter-gatherer population from the rainforests of Southern Thailand, offer a unique context for investigating how demographic history, genetic drift, and pathogen-driven selection shape human leucocyte antigen (HLA) diversity. Using high-coverage whole-genome data from 21 individuals (12 unrelated), we genotyped HLA alleles with HLA-HD and T1K, identifying 32 alleles in classical and 14 in non-classical HLA genes. Although overall HLA diversity was comparatively low, a few alleles at each locus occurred at high frequency, mirroring patterns observed in other small, isolated populations. Principal-component analysis clustered the Maniq with other Austroasiatic-speaking Semang hunter-gatherers (Jehai, Kintaq) on the Malay Peninsula and, intriguingly, with the Austronesian-speaking Tao of Taiwan, indicating shared immunogenetic features across linguistic boundaries. Despite reduced diversity, multiple loci bore signatures of both long-term balancing and recent positive selection. Several SNPs under selection were in complete linkage disequilibrium with eQTLs known to influence responses to hepatitis B virus (HBV) and other pathogens, suggesting that pathogen-driven pressure-in particular HBV-may have contributed to recent HLA evolution in the Maniq. These findings provide critical insights into how demographic constraints and pathogen landscapes converge to shape HLA diversity and evolution. In light of increasing infectious disease burdens in indigenous communities, our results underscore the importance of studying small, isolated populations to better understand the adaptive significance of HLA genes.

关键词： Bioinformatics  

摘要： Background: Human Leukocyte Antigens (HLA) play central roles in histocompatibility and immune system functions, including antigen presentation. Accurate typing of Class I and II HLA genes is crucial for transplant tissue matching, characterising autoimmune diseases and informing cancer immunotherapy. Clinical serology and PCR-based testing are the gold standards for HLA typing, but offer only single-field resolution (e.g., HLA-A*11). Whole genome sequencing (WGS) and RNA sequencing (RNA-seq) can achieve higher, three-field resolution (e.g., HLA-A∗11:01:01), although some HLA genes can be challenging to type from sequencing data. With the increasing use of germline WGS, tumour WGS and tumour RNA-seq in cancer patient care, there is an opportunity to combine these three dataset types to improve HLA typing accuracy and confidence, and to identify clinically relevant HLA type changes in tumours. To achieve this, we developed consHLA, a tool that employs this consensus HLA typing approach. Results: We obtained matched germline and tumour WGS and RNA-seq data from 86 high-risk paediatric cancer patients (76 brain cancers, 10 leukaemias) from the ZERO Childhood Cancer precision medicine program. We examined 10 HLA typing packages, selecting HLA-HD to develop our consHLA workflow as HLA-HD can employ all three dataset types, analysing both Class I and II HLA genes at three field resolution. Using consHLA we achieved 97.9% concordance with gold standard HLA test results. We observed 90.5% allele consistency across the three sequencing NGS inputs. Typing inconsistencies in at least one of 12 clinically relevant HLA genes were observed in 29 of the brain tumour cases. 32% of these had clinically relevant explanations. To assist clinically, we implemented consHLA as a fully automated workflow producing a clinician-friendly HLA-typing report. Conclusions: To leverage cancer patient germline and tumour WGS and tumour RNA-seq data we developed an automated workflow, consHLA, that

关键词： Diabetic kidney disease   Neutrophil extracellular traps   Inflammation   Subtype   IL-33  

摘要： BackgroundChronic inflammation is well recognized as a key factor related to renal function deterioration in patients with diabetic kidney disease (DKD). Neutrophil extracellular traps (NETs) play an important role in amplifying inflammation. With respect to NET-related genes, the aim of this study was to explore the mechanism of DKD progression and therefore identify potential intervention *** NET-related DEGs were screened via differential expression analysis and three machine learning methods, namely, LASSO, SVM-RFE and random forest. Consensus clustering was performed to analyze NET-related subtypes in DKD patients. KEGG enrichment analysis, GSEA, GSVA, ssGSEA and ESTIMATE were conducted to explore the molecular features of DKD patient subtypes. Leveraging single-nucleus RNA-seq datasets, the "scissor" and "bisqueRNA" algorithms were applied to identify the composition of renal cell types in DKD patient subtypes. Soft clustering analysis was performed to obtain gene groups with similar expression patterns during the development and progression of DKD. The correlations between hub NET-related DEGs and clinical parameters were mined from the Nephroseq V5 database. The core gene among the hub NET-related DEGs was selected by calculating semantic similarity. "Cellchat" algorithm, immunostaining, ELISA and flow cytometry were performed to explore the expression and function of the core gene. The Drug-Gene Interaction Database (DGIdb) was searched to identify candidate *** hub NET-related DEGs, namely, ACTN1, ITGB2, IL33, HRG, NFIL3 and CLEC4E, were identified. On the basis of these 6 genes, DKD patients were classified into 2 clusters. Cluster 1 patients, with higher NET scores, were evidently more immune-activating than those of cluster 2. Markedly increased numbers of immune cells, fibroblasts and proinflammatory proximal tubular cells were observed in cluster 1 but not in cluster 2. Cluster 1 also represented a more clinically advanced

关键词： Allogeneic hematopoietic stem cell transplantation   Unrelated donors mismatch   Survival  

摘要： Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important treatment option for hematologic diseases. However, limited studies have evaluated the prognosis of patients receiving single human leukocyte antigen (HLA) mismatched unrelated donor allo-HSCT (HLA 9/10 MMUD-HSCT) compared to those receiving fully matched unrelated donor allo-HSCT (10/10 MUD-HSCT). This study retrospectively analyzed 126 cases of unrelated donor allo-HSCT (URD-HSCT) at our center, in which anti-human thymocyte globulin (ATG, 7.5 mg/kg) was used as a graft-versus-host disease (GVHD) prophylaxis strategy. The MUD-HSCT group had a significantly lower incidence of grade II-IV acute GVHD (13.89% vs. 35.19% in the MMUD-HSCT group, p = 0.005). In contrast, the incidence of moderate-to-severe chronic GVHD (cGVHD) did not differ significantly between the two groups (16.67% vs. 29.63%, p = 0.083). The median follow-up time was 16.98 months (range: 7.88-38.55). There were no significant differences between the two groups in the 1-year cumulative incidence of relapse (CIR) (p = 0.707), 3-year CIR (p = 0.764), 1-year disease-free survival (DFS) (p = 0.954), 3-year DFS (p = 0.888), 1-year overall survival (OS) (p = 0.611), 3-year OS (p = 0.796), 3-year non-relapse mortality (NRM) (p = 0.711), or GVHD-free relapse-free survival (GRFS) (p = 0.546). The estimated median OS and DFS times were not reached in either group. In conclusion, under an ATG-based GVHD prophylaxis regimen, HLA 9/10 MMUD-HSCT is a viable alternative donor option, offering comparable clinical outcomes to those of fully matched unrelated donor HSCT.