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摘要： Purpose: Ewing sarcoma, in contrast to some adult sarcoma subtypes, generally does not respond to single-agent immunotherapy targeting PD1. The features of Ewing sarcoma that preclude the effectiveness of immunotherapy remain largely unknown. To address this question, we utilized biopsies from patients with Ewing sarcoma obtained before and after pembrolizumab (anti-PD1) therapy from the phase II clinical trial SARC028 to interrogate the Ewing tumor microenvironment and features associated with resistance to checkpoint *** Design: We utilized multiplexed immunofluorescence, spatial proteomics, and spatial transcriptomics to analyze paired pretreatment and 8-week posttreatment biopsy specimens from patients with Ewing sarcoma enrolled in ***: Pembrolizumab therapy did not alter the quantity of immune cell infiltration in Ewing tumor biopsies. Analysis of tumor-associated protein markers revealed increased immunoregulatory markers after pembrolizumab. Spatial transcriptomics identified 10 cellular neighborhoods (CN) across patients consisting of specific cell subsets. CN10 was consistently observed across patients with a poor response. This CN was enriched for a tumor subpopulation with a high TGF-beta response, low IFN response, and low HLA class I expression. IFN response, HLA class I expression, and overall immune infiltration were ***: Analyses of paired Ewing sarcoma tumor samples from SARC028 reveal an immunosuppressive triad, the disruption of which should be pursued to improve antitumor immunity. This work highlights the unique insight that can be gained from the analysis of paired patient Ewing sarcoma tumor biopsy samples from clinical trials.

关键词： interferon-gamma   JAK2/STAT3 signaling pathway   jawbone marrow stromal cells   methyltransferase-like 3   osteogenic differentiation   postmenopausal osteoporosis  

摘要： To investigate whether interferon-gamma (IFN-gamma) alleviates postmenopausal osteoporosis (POP) by regulating METTL3 via the JAK2/STAT3 pathway to enhance osteogenic differentiation of jawbone marrow stromal cells (JBMSCs). Ovariectomized (OVX) rats received IFN-gamma (5000 IU/dose, 3x/week for 24 weeks), with jawbone mass assessed via micro-CT and HE staining. JBMSCs were cultured, and osteogenic differentiation under IFN-gamma (optimal concentration: 10 ng/mL) was evaluated using qRT-PCR, ALP/alizarin red staining, and CCK-8. METTL3's role was analyzed via lentiviral overexpression (OE-METTL3) or knockdown (sh-METTL3). JAK2/STAT3 pathway activity was tested using AG490 (JAK2 inhibitor) and Western blot for phosphorylated JAK2/STAT3. IFN-gamma reduced alveolar bone loss in OVX rats, increased osteocytes, and decreased osteoclasts. In JBMSCs, 10 ng/mL IFN-gamma upregulated osteogenic genes (Runx2, OPN, OPG) and mineralization. METTL3 expression was elevated by IFN-gamma;sh-METTL3 suppressed Runx2, while OE-METTL3 reversed OVX-induced osteogenic inhibition. IFN-gamma activated JAK2/STAT3 signaling, but AG490 reduced both osteogenic gene expression and METTL3 levels. METTL3 overexpression amplified JAK2/STAT3 phosphorylation, synergizing with IFN-gamma to enhance osteogenesis. IFN-gamma activates the JAK2/STAT3 pathway to drive METTL3 transcription, upregulating osteogenic genes and mitigating jawbone loss in POP. METTL3 overexpression counteracts estrogen deficiency-induced osteogenic suppression and forms a positive feedback loop with JAK2/STAT3. AG490's complete blockade of IFN-gamma/METTL3 effects confirms the JAK2/STAT3-METTL3 axis as central to bone immune metabolism, highlighting therapeutic potential for targeting this pathway in POP.

关键词： ulcerative colitis   neutrophil extracellular traps   anti-TNF-alpha   machine learning   predictive model  

摘要： Background Neutrophil extracellular traps (NET) play a pivotal role in the pathogenesis of ulcerative colitis (UC) and may contribute to the impaired response to anti-tumor necrosis factor alpha (TNF-alpha) therapies. However, the functional implications of NET-associated genes in UC remain poorly understood. This study aims to identify key NET-associated molecular signatures in UC, develop diagnostic models based on NET-related biomarkers, and construct predictive models for response to anti-TNF-alpha therapies (infliximab and golimumab). Methods NET-associated genes were obtained from the Kyoto Encyclopedia of Genes and Genomes, whereas UC-related gene expression datasets were retrieved from the Gene Expression Omnibus. Unsupervised consensus clustering based on NET-related genes was used to stratify patients with UC into molecular subtypes. The CIBERSORT algorithm and gene set variation analysis were employed to characterize immune cell infiltration and biological pathway activity across clusters. Hub genes were identified using weighted gene co-expression network analysis and machine learning algorithms. Spearman correlation analyses were performed to assess associations between hub genes, immune cell infiltration, and clinical disease activity. A diagnostic model for UC and a prognostic model for anti-TNF-alpha treatment response were developed using hub genes identified through least absolute shrinkage and selection operator regression. Results Based on 33 NET-associated genes, patients with UC were stratified into two distinct molecular clusters (C1 and C2). Cluster C1 exhibited a pronounced NET signature, characterized by significantly elevated neutrophil infiltration (p < 0.001) and activation of inflammatory signaling pathways, including IL-2/STAT5, TNF-alpha/NF-kappa B, and IL-6/JAK/STAT3. Notably, C1 was associated with a significantly higher rate of non-response to anti-TNF-alpha therapy (57.4% vs. 22.0% in C2, p = 0.003). A diagnostic model for UC was

关键词： HLA   HLA-DRB1*13:371   next-generation sequencing   novel allele  

摘要： The novel allele HLA-DRB1*13:371 differs from HLA-DRB1*13:02:01:01 by one nucleotide substitution in codon 127 in exon 3.

关键词： 补肺汤   玉屏风散   环磷酰胺   类风湿关节炎   肺间质病变   血清Ⅱ型肺泡细胞表面抗原   白细胞介素-27  

摘要： 目的：探究补肺汤合玉屏风散加减连环磷酰胺治疗类风湿关节炎肺间质病变的疗效及对血清KL-6、IL-27的影响。方法：选取2024年2月—2025年2月海南医学院第一附属医院住院治疗的类风湿关节炎肺间质病变患者100例，随机数字表奇偶位数分组分为试验组50例与对照组50例。对照组予以注射用环磷酰胺，试验组在对照组的基础上予以补肺汤合玉屏风散加减，两组均连续治疗8周。对比两组中医证候评分、临床疗效、类风湿关节炎疾病活动评分(DAS-28)、呼吸困难症状及肺高分辨率CT(HRCT)评分、血清白细胞介素27(IL-27)、Ⅱ型肺泡细胞表面抗原(KL-6)。结果：治疗后，两组中医证候评分、DAS-28、HRCT评分、血清KL-6、IL-27水平有所降低(P＜0.05)；试验组各项中医证候评分、DAS-28、HRCT评分、血清KL-6、IL-27水平较对照组低(P＜0.05)，总有效率较对照组高(P＜0.05)。对照组不良反应发生率为6.00%与试验组不良反应发生率为4.00%相比无统计学差异(P＞0.05)。结论：补肺汤合玉屏风散加减联合环磷酰胺联合疗法应用于类风湿关节炎肺间质病变中，不仅可增强疗效、改善患者症状、控制肺间质病变进展，其作用机制与下调血清KL-6和IL-27水平具有相关性。

关键词： Hematopoietic stem cell transplant   eplet   HLA eplet mismatch   epitope   haploidentical transplantation   reduced-intensity conditioning   outpatient transplantation  

摘要： BackgroundMolecular typing before hematopoietic stem cell transplantation (HSCT) at the eplet level is an emerging method to optimize HLA *** and methodsPatients who received outpatient haploidentical HSCT (Haplo-HSCT) from a sibling after reduced intensity conditioning (RIC) were studied. HLA class I and II mismatched eplets (MEs) load was determined using HLAMatchmaker software. A cutoff > or < 10 MEs was used to assess ***114 patients were studied. A locus B MEs load > 10 was associated with decreased overall survival (OS), (p = 0.049), and increased graft failure (GF) (p = 0.004). Mortality was higher with > 10 MEs in HLA-I locus B (p = 0.025), and HLA-II DRB1 (p = 0.026);chronic GVHD was higher with > 10 MEs in DRB1 (p = 0.009). Anti-HLA donor-specific antibodies (DSA) were more frequent in recipients with > 10 MEs load at locus C (p = 0.021) and DRB1 (p = 0.002). MEs load > 10 at locus C and DRB1 were associated with anti-HLA DSA. Infection (p = 0.012), DSA (p = 0.014), and relapse (p = 0.001) were associated with lower OS, while multitransfusion (p = 0.035), aGVHD (p = 0.035) and infection (p = 0.021) with reduced event-free survival (EFS).ConclusionHLA MEs load > 10 in locus B was associated with reduced OS, and in locus DRB1 with higher death rate and cGVHD after outpatient sibling haplo-HSCT using RIC.

关键词： span>Hepatocytesregenerationsingle cell transcriptomicsliver 3D cultureIL-4interleukin-4PCLSPrecision-Cut Liver SlicesqPCRquantitative Polymerase Chain ReactionsnRNA-seqsingle nucleus RNA-sequencingscRNA-seqsingle cell RNA-sequencingTAAthioacetamideHTKhistidine-tryptophan-ketoglutarateH&   E   span>hematoxylin and eosinTUNELterminal deoxynucleotidyl transferase dUTP nick end labellingCSTCHAPS with salt and TrisFACSfluorescence activated cell sortingCHAPS3-((3-cholamidopropyl) dimethylammonio)-1-propanesulfonateTrishydroxymethyl aminomethaneUMAPUniform Manifold Approximation and ProjectionLSECsLiver Sinusoidal Endothelial CellsIHCimmunohistochemistry  

关键词： Introgression line   Fruit shape   Fruit size   Epistasis   Marker-assisted selection   QTL  

摘要： Traditional melon varieties with high value in local markets are grown in the Iberian Peninsula. However, their cultivation is declining, being replaced by modern varieties. Five high quality traditional were selected ('Piel de Sapo', 'Amarillo', 'Rochet', 'Tendral' and 'Blanco') to modify their fruit morphology in order to make them more appealing for consumer using a set of introgression lines (IL) from the accessions 'Vedrantais' (VED, cantaloupe, France), PI 273438 (DUD, Dudaim, Iraq), Ames 24,297 (TRI, wild melon, Pakistan), and PI 124112 (CALC, acidulus, India) in the genetic background of two 'Piel de Sapo' cultivars. The ILs contained QTLs that induced round fruits (CALC8-1, DUD4-2, VED11-2), large fruits (TRI05-2), and small fruits (TRI08-2, DUD1-2, DUD4-2). Hybrids between ILs and traditional varieties were studied to verify the effect of ILs in the traditional genetic backgrounds and IL x genetic background (IL x GB) interactions. The ILs with more stable effects were TRI08-2 (reducing fruit weight), TRI05-2 (increasing fruit weight), and CALC8-1 (round shape). ILxGB interactions were also found, mainly in VED11-2 and DUD4-2 for fruit weight. These results allowed us to identify the best ILs to modify fruit morphology in the traditional varieties by breeding programs. Additionally, the identification of IL x GB interactions for some ILs, such as VED11-2 and DUD4-2 for fruit weight provides an experimental system to shed insights into the genetic basis of QTLxGB interactions.

关键词： 胰腺炎   肠内营养   炎症   胃肠道微生物组   时间因素   细胞因子   菌群失调   随机对照试验  

摘要： 目的探究早期肠内营养(EEN)对急性胰腺炎(AP)患者的炎症反应和肠道菌群的影响。方法选择2023年1月至2024年9月的180例AP患者,根据随机表法分为观察组A与观察组B,每组90例;给予两者常规治疗外,另外48 h内给予观察组A肠内营养治疗,24 h内给予观察组B肠内营养治疗;比较两者治疗前后血清炎性因子IL-1β、IL-6、TNF-α水平变化以及肠道菌群大肠杆菌、肠球菌、产气荚膜梭菌、乳酸杆菌以及拟杆菌的变化。结果与48 h内启动肠内营养相比,24 h内启动肠内营养可显著降低AP患者血清IL-1β、IL-6、TNF-α水平(P<0.01),并有效减少大肠杆菌、肠球菌及产气荚膜梭菌丰度,同时增加乳酸杆菌与拟杆菌丰度(P<0.01)。结果表明,较早启动肠内营养具有更优的抗炎和肠道菌群调节效果。结论EEN可以有效治疗AP,降低患者血清炎性因子IL-1β、IL-6、TNF-α和肠道菌群中的不良菌群,提高肠道菌群中的益生菌,且时间越早,效果越好。