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关键词： ETV6   Fusion   Chronic eosinophilic leukemia   Hypereosinophilia   RNA Sequencing  

摘要： Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative neoplasm. Diagnosis of CEL is often challenging, notably because of the lack of recurrent and specific molecular event. We report here a case of CEL occurring in a 49-year-old man who presented a persistent hypereosinophilia (HE) associated with anemia and thrombopenia. Karyotyping showed a translocation t(5;12)(q31;p13). Targeted RNA Sequencing identified a novel ETV6::RAPGEF6 fusion gene, confirmed by RT-PCR. Despite several lines of treatment, the patient died after 16 months of duration with transformation to acute myeloid leukemia (AML).Contrary to myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), where fusion genes are both class defining and involve tyrosine kinase genes as the 3' partner, fusion genes are exceedingly rare in non-MLN-TK myeloid malignancies with HE. The most reported fusion gene is ETV6::ACSL6, in rare cases. Previously, overexpression of IL3 (interleukin 3) has been described in myeloid neoplasms with ETV6::ACSL6 (previously named ACS2). In our case of CEL with the ETV6::RAPGEF6 fusion, we also demonstrated overexpression of IL3, which could potentially result from the proximity of the IL3 gene to RAPGEF6, similar to what is observed with ACSL6 and IL3. The use of RNA sequencing in routine diagnosis of CEL could provide evidence for clonal event such as gene fusion, improving diagnosis as well as prognosis and therapeutic approaches.

关键词： 酵母微囊   纳米乳   免疫佐剂   亚单位疫苗   细胞免疫应答  

摘要： 利用酵母衍生的微囊多级装载纳米乳佐剂MF59和抗原， 以解决MF59佐剂不能直接包载抗原以及诱导细胞免疫能力不足的问题。利用强酸碱法制备酵母微囊 （yeast microcapsules， YC）， 其具有多孔、中空的结构和较好的佐剂效应。将聚合物聚己内酯-聚乙烯亚胺 （polycaprolactone-polyethyleneimine， PCL-PEI） 修饰MF59纳米乳获得正电性的乳粒， 通过静电力驱动使乳粒自发沉积到YC中， 并进一步吸附抗原鸡卵清白蛋白 （ovalbumin， OVA）， 得到共载抗原和佐剂的疫苗YC-MF59-OVA。YC-MF59-OVA基于囊壳上β-葡聚糖可被抗原提呈细胞 （antigen presenting cells， APCs） 识别而内吞， 同时在接种部位募集抗原提呈细胞， 进而有效激活机体免疫响应， 使血清中lgG、lgG1、lgG2a抗体水平相比游离OVA升高了2～3倍; 诱导了显著高于OVA的IFN-γ+CD8+、IL-4+CD4+T细胞免疫应答， 刺激脾组织中记忆性CD44+CD62L+T细胞比例显著升高。本动物实验方案经遵义医科大学实验动物伦理委员会审核批准 （批准号: ZMU21-2407-169）。以上结果表明， YC-MF59-OVA能够激活强效的体液免疫应答和细胞免疫应答， 证实YC能够显著弥补纳米乳佐剂的不足， 为后续疫苗递送系统的开发提供新的参考。

关键词： Acute kidney injury (AKI)   double- negative (DN T cells)   IL-7   renal tubular epithelial cells (RTEC)   gamma-chain cytokines  

摘要： BackgroundPrevious studies have demonstrated that double-negative (DN) alpha beta T cells play an important role in immune responses during ischemic acute kidney injury (AKI). Here, we investigate the role of gamma-chain cytokines in driving DN T cell proliferation in steady state and AKI, focusing on IL-2, IL-7, and *** assessed DN T cell proliferation in vitro in response to IL-2, IL-7, and IL-15, with co-culture experiments using renal tubular epithelial cells (RTECs) and IL-7 blockade. In vivo, wild-type and IL-7r knockout mice were studied to evaluate the impact of IL-7 on DN T cell expansion and kidney function during AKI. Human RTECs confirmed the relevance of these *** three cytokines promoted DN T cell proliferation in vitro, with IL-7 inducing the most robust expansion. Co-culture experiments showed RTECs as a key IL-7 source, and blockade reduced DN T cell expansion. In vivo, IL-7 complexes administered to wild-type mice increased DN T cells and selectively expanded the PD-1+ subset. IL-7 deficiency worsened renal outcomes during AKI. Human RTECs activated peripheral human DN T cells in *** results establish IL-7 as pivotal for DN T cell expansion and highlight RTECs' role in DN T cell homeostasis.

关键词： Hepatocellular carcinoma   Sorafenib   Resistance   Pharmacogenomics   IL-23R   ATG-10  

摘要： Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Sorafenib is the first FDA-approved systemic therapy for advanced HCC. This study investigates the influence of IL-23R (rs7517847) and ATG-10 (rs10514231) genetic polymorphisms on Sorafenib response, survival outcomes, average tolerable dose, and adverse events. This prospective open-label cohort study included 100 HCC patients, assessing IL-23R and ATG-10 genotypes via real-time polymerase chain reaction (RT-PCR). Patient's responses were evaluated using modified RECIST criteria. Statistical analyses evaluated the association of genetic variants with response, progression-free survival (PFS), overall survival (OS), average tolerable Sorafenib dose, and adverse events. IL-23R TT carriers had the highest Sorafenib response rate (80%) compared to GT (13.3%) and GG (6.7%) (P = 0.021), while ATG-10 TT carriers had a 13.9-fold increased response likelihood (P = 0.001). The T allele in ATG-10 significantly predicted longer PFS (P = 0.025) and OS (P = 0.011), suggesting a potential prognostic role. IL-23R GG carriers received significantly higher Sorafenib doses than TT (P = 0.0174) and GT (P = 0.0227), whereas ATG-10 had no effect on dosage. However, its CT genotype was significantly associated with a higher risk of Hand-Foot Syndrome (P = 0.012), and independent of dose (P = 0.0018). IL-23R and ATG-10 polymorphisms influence Sorafenib response, survival, and tolerability in HCC patients. Genetic screening may improve personalized treatment strategies by optimizing Sorafenib efficacy and minimizing *** trial was registered on *** with registration number NCT06030895, registered on "September 11th, 2023," retrospectively.

关键词： 细胞免疫疗法   三阴性乳腺癌   荟萃分析   Cellular Immunotherapy   Triple Negative Breast Cancer   Meta-Analysis  

摘要： 目的：目前，临床上关于CIK免疫治疗对TNBC患者影响的数据有限且有数个关于三阴性乳腺癌化疗联合细胞免疫治疗的回顾性研究。因此，我们进行了荟萃分析，旨在评估细胞免疫治疗联合化疗对三阴性乳腺癌患者有效性及安全性的影响。方法：用计算机在线检索PubMed、Embase、the Cochrane Library 三个数据库，严格按照纳入及排除标准，筛选出在2024年10月19前已发表的在三阴性乳腺癌化疗中对比了联合细胞免疫治疗与不联合细胞免疫治疗对三阴性乳腺癌患者影响的研究，采用纽卡斯尔–渥太华量表(Newcastle-Ottawa Scale, NOS)对最终纳入的文献进行质量评价，用Engauge Digitizer提取软件进行资料提取，之后用STATA 18.0软件进行相关的统计分析。结果：按照纳入标准严格筛选后，最终纳入五项回顾性病例对照研究，总共包含1248名患者。Meta分析结果表明与化疗相比，细胞免疫治疗联合化疗显著提高了TNBC患者的总生存期(OS)和无病生存期(DFS)。联合治疗与IIb期和III期较好的OS有显著相关性，而与I期和IIa期无显著相关性。联合治疗对于各个分期患者的DFS均无显著延长。接受 ≥ 6个周期细胞免疫治疗的患者有更高的OS和DFS。结论：本meta分析结果表明，三阴乳腺癌的细胞免疫治疗联合化疗可以改善患者的OS和DFS，晚期患者获益更为显著，并且 ≥ 6个周期细胞治疗效果甚佳。细胞免疫治疗联合化疗无3级以上不良反应发生且经对症治疗后得到缓解，表明联合治疗是安全的。

关键词： Vestibular schwannoma   Great auricular nerve   Sensorineural hearing loss   Cytokines   Chemokines   Tumor-conditioned media   Perilymph   Blood  

摘要： BackgroundVestibular schwannoma (VS) is an intracranial tumor arising from the Schwann cells of the vestibular nerve and is an important cause of sensorineural hearing loss (SNHL) in humans. The mechanisms underlying this SNHL are incompletely understood and currently, there are no drugs FDA approved specifically for VS. This knowledge gap significantly limits the development of effective treatments aimed at preventing, stabilizing, or reversing VS-induced *** identify effector molecules involved in VS-induced SNHL, we analyzed 47 immune-related factors secreted by tumor tissue in over 50 patients with sporadic VS and studied their correlation with preoperative hearing ability and tumor size. The most promising effector molecules were validated in vivo in an anatomically accurate mouse model of VS, and in vitro with mouse fibroblasts (L929) and auditory cell lines representing pro-sensory precursors of hair cells (UB-OC1) and auditory neuroblasts (US-VOT-N33).ResultsWe demonstrated that VS-induced SNHL was linked to increased secretion of TNF-alpha, IL-2R, CD163, eotaxin, and HGF, while larger tumor size was associated with higher levels of TNF-alpha, TNF-R2, IL-1 alpha, IFN-alpha, MIP-1 beta, and IL-21 secretion. We identified heterogeneity among VS tumors in their capacity to secrete TNF-alpha. Tumors with high levels of TNF-alpha secretion released cytokines and chemokines that significantly correlated with poor hearing (TWEAK and eotaxin) or better hearing (LIF, GRO-alpha, MIP-1 alpha, MIP-3 alpha, and IL-1 alpha). Among these, TWEAK was notably abundant, with levels exceeding those in normal nerve tissue, elevated in patients with non-serviceable hearing and strongly linked to poor hearing in patients with TNF-alpha high-secreting tumors. In vivo, we demonstrated that VS-secreted factors reach the inner ear, with elevated TNF-alpha and TWEAK in the perilymph and blood of tumor-bearing mice with impaired hearing. In vitro, TWEAK amplified TNF-alpha -m

关键词： colonization factor   cytokine   enterotoxigenic Escherichia coli   toxin  

摘要： Enterotoxigenic (ETEC) produces two types of enterotoxins, LTs and STs, as well as several colonization factors (CFs), including CS21, CS3 fimbriae, and flagellar structures. This study investigated how these structures contribute to ETEC colonization and the immune response in HT-29 and HuTu-80 intestinal cells. ETEC strains with single, double, and triple mutations in the , , and genes were generated and confirmed using PCR and Western blotting. The colonization of HT-29 and HuTu-80 intestinal cells by the ETEC E9034A strain, which was fully sequenced using a hybrid approach involving both Illumina and Oxford Nanopore technologies, was used to generate the mutant and recombinant proteins. The colonization and adherence of E9034A and its mutants were assessed through colony-forming unit (CFU) counts. Cytokine levels were assessed using flow cytometry and analyzed via FlowJo 7.6.1. Quantitative analysis revealed that the absence of the , , and genes significantly ( < 0.01) reduced ETEC adherence to HT-29 and HutU-80 cells. In addition, only ETEC strains expressing the FliC protein induced IL-8 secretion. These findings suggest that LngA, CstH, and FliC in ETEC E9034A enhance adherence to intestinal cells and trigger the release of IL-8.

关键词： HLA   Hidradenitis suppurativa   PSO-SH   Psoriasis   co-occurrence   genetics   non-HLA  

摘要： BACKGROUND:Select patients are diagnosed with both, psoriasis (PSO) and hidradenitis suppurativa (HS), leading to a unique disease pattern. Genetic risk factors remain unidentified. METHODS:The study harnessed an international collection of patients with psoriasis and HS (PSO-SH). Clinical and genetic data was collected and analyzed. RESULTS:87 PSO-SH patients (70% female) were identified. They had a high number of comorbidities (89%), and worse general physical health compared to PSO-only (OR 3.09 95%CI 1.56-6.12) or HS-only (OR 2.5, 95%CI 1.23-5.00) patients. PSO-SH patients were at significantly higher risk of having Crohn's disease (OR 4.6-11.9; 95% CI). Data revealed the highest overall genetic risk score for PSO-SH patients (PSO-PRS; 108.22), followed by PSO (101.18), HS (99.84), and healthy controls (98.58). High non-HLA scores were associated with an increased risk for developing both psoriasis and HS, indicating a distinct biological profile compared to HS-only and PSO-only individuals. LIMITATIONS:Some clinical information was collected retrospectively. CONCLUSIONS:This study highlights a shared genetic susceptibility of HS and psoriasis at non-HLA loci. Recognizing PSO-SH patients as a distinct patient group with high morbidity and increased risk for developing Crohn's disease will help to improve patient management.

关键词： Eczema   Vitamin   TG2   IL-4   IL-13  

摘要： The study aims to examine fluctuations in the levels of serum vitamin A, 25-(OH)D-3, TG2, IL-4, and IL-13 in pediatric eczema patients and explore how these changes relate to the severity of the condition. This retrospective study analyzed the clinical data of 159 children with eczema admitted to the hospital from May 2023 to October 2024 as the experimental group. The patients were divided into groups according to the severity of the disease: mild group(<= 25 points, n = 45), moderate group(25-50 points, n = 72) and severe group(>50 points, n = 42). Collect each group of serum serum vitamin A, 25- (OH) D3, TG2, IL-4, and IL-13 levels and analyze them. The improvements in serum vitamin A, 25-(OH)D3, TG2, IL-4, and IL-13 levels in each group of children after 3 months of treatment were further analyzed. As eczema severity escalated, there was a progressive decline in Vit A and 25-(OH)D3 levels, while TG2, IL-4, and IL-13 levels correspondingly rose (P < 0.05). Pearson correlation analysis revealed a significant negative correlation between serum Vit A and 25-(OH)D3 levels and the SCORAD scores in children with eczema (P < 0.05). Conversely, TG2, IL-4, and IL-13 levels exhibited positive correlations with the SCORAD scores (P < 0.05). 25-(OH)D3 had the highest AUC for diagnosing the severity of eczema, which was significantly better than serum vitamin A, TG2, IL-4, and IL - 13 ( all P < 0.05 ). After 3 months of treatment, the serum levels of vitamin A, 25-(OH)D3, TG2, IL-4, and IL-13 in all groups were significantly improved (P < 0.05). Vit A, 25-(OH)D3, TG2, IL-4, and IL-13 correlate with the severity of eczema symptoms. The severity of the disease can be evaluated clinically according to the changes in these serum indicators, and the clinical application value is high.

摘要： Type I Interferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans;meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition.