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摘要： The article by Ling et al entitled “Busulfan Plus Fludarabine Compared With Busulfan Plus Cyclophosphamide for AML Undergoing HLA-Haploidentical Hematopoietic Cell Transplantation: A Multicenter Randomized Phase III Trial” ( Journal of Clinical Oncology 10.1200/JCO.23.00101 ) was published online June 19, 2023, with an error. The Data Sharing Statement provided was inaccurate. A new version has been provided. This has been corrected as of August 13, 2024. The authors apologize for the error.

关键词： subcortical small-vessel disease   IL-6   IL-17A   cerebrospinal fluid   albumin quotient   ventricles   neuropsychological profiles   MRI   biomarkers  

摘要： Background/Objectives: Low-grade inflammation in the form of microglial activation may be involved in neurodegenerative and vascular dementias. Subcortical small-vessel disease (SSVD) is the main form of vascular dementia, associated with brain barrier dysfunction and endothelial and monocyte activation. IL-6 and IL-17A are known proinflammatory cytokines that contribute to the disruption of blood-brain barrier integrity and microvascular dysfunction, features that are central to SSVD pathophysiological pathways. We herein compared cerebrospinal fluid (CSF) IL-6 and IL-17A concentrations in SSVD and AD patients as well as control subjects and examined the potential associations among IL-6 and IL-17A levels with cognitive and Mu R Iota changes. The albumin quotient (Qalb) was also calculated. Methods: CSF IL-6 and IL-17A (18 SSVD, 17 AD, and 12 healthy controls) were measured with solid-phase sandwich ELISAs, while albumin levels were measured by immunonephelometry. MMSE, FAB, and the CLOX tests were used for cognitive assessment and MRI was used for atrophy and white matter hyperintensities. Results: Significantly elevated CSF levels of Qalb and IL-6 were found in SSVD patients compared to both AD (p = 0.02) and controls (p = 0.002), respectively. Moreover, CSF IL-6 levels displayed a significant inverse correlation with CLOX2 scores (r = -0.641, p = 0.02), as well as a positive correlation with the total normalized CSF volume (r = 0.7, p = 0.01). CSF IL-17A levels were found to be reduced in SSVD patients, compared to controls and AD patients (p < 0.0001 and p = 0.002, respectively). The IL-6/IL-17A ratio with a cut-off value > 1.004 displayed a sensitivity of 83.33% (95%CI;60.78% to 94.16%) and a specificity of 68.97% (95%CI;50.77% to 82.72%) for the discrimination of SSVD from AD patients and controls. Conclusions: In the present pilot single-center study, we found increased CSF IL-6 and IL-6/IL-17A ratio levels in SSVD patients that correlated with reduced score

关键词： 血红蛋白/红细胞分布宽度比值   预后营养指数   结直肠癌   诊断效能  

摘要： 目的　探讨术前血红蛋白(Hb)/红细胞分布宽度(RDW)比值(HRR)、预后营养指数(PNI)及癌胚抗原(CEA)在结直肠癌诊断中的应用价值。方法　回顾性收集2019年9月－2023年12月安徽医科大学附属巢湖医院收治的224例结直肠癌患者，设为结直肠癌组，该院同期收治的207例结直肠良性疾病患者设为对照组。比较两组患者的一般资料，外周血红细胞、白细胞、中性粒细胞、淋巴细胞计数及CEA水平，并计算HRR、PNI。分析结直肠癌发生的影响因素，对筛选出的变量进行多重共线性分析，将方差膨胀因子(VIF)<5的变量纳入多因素二元logistic回归分析筛选结直肠癌发生的独立影响因素，并将HRR、PNI及CEA通过二元logistic回归分析构建联合模型；绘制受试者操作特征(ROC)曲线，分析HRR、PNI、CEA单独及联合诊断结直肠癌的效能，采用Calibration校准曲线、决策曲线(DCA)评价联合模型的校准度及临床实用性；采用Spearman秩相关分析结直肠癌患者营养状态(根据PNI值进行评估)与不同营养指标[体重指数(BMI)、Hb、白蛋白(ALB)、红细胞计数及淋巴细胞计数]的相关性。结果　与对照组比较，结直肠癌组红细胞计数、HRR、PNI及ALB、Hb水平明显降低，RDW、CEA水平明显升高，差异均有统计学意义(P<0.001)。二元logistic回归分析显示，ALB、CEA、HRR及PNI为结直肠癌发生的独立影响因素(P<0.05)。ROC曲线分析显示，HRR单独诊断结直肠癌的曲线下面积(AUC)最大(0.721)，PNI的敏感度最高(64.2%)；HRR、PNI与CEA联合诊断结直肠癌的AUC为0.784，敏感度和特异度分别为67.0%、84.1%，内部验证及Calibration校准曲线、DCA分析显示联合模型的区分度、一致性及临床效能较好。Spearman秩相关分析显示，Hb、ALB水平及红细胞、淋巴细胞计数与PNI之间存在明显相关性(P<0.05)，且结直肠癌营养状态越差(PNI值越低)，营养指标数值越低。结论　HRR及PNI对结直肠癌具有重要的诊断价值，与CEA联合应用可提高诊断效能，且PNI能够较好地评估结直肠癌患者的营养状况。

关键词： Inflammation   Innate immunity   Noncoding RNAs   Pulmonology   RNA processing  

摘要： Idiopathic pulmonary fibrosis (IPF) causes remodeling of the distal lung. Pulmonary remodeling is histologically characterized by fibrosis, as well as appearance of basal cells;however, the involvement of basal cells in IPF remains unclear. Here, we focus on the long noncoding RNA MIR205HG, which is highly expressed in basal cells, using RNA sequencing. Through RNA sequencing of genetic manipulations using primary cells and organoids, we discovered that MIR205HG regulates IL-33 expression. Mechanistically, the AluJb element of MIR205HG plays a key role in IL-33 expression. Additionally, we identified a small molecule that targets the AluJb element, leading to decreased IL-33 expression. IL-33 is known to induce type 2 innate lymphoid cells (ILC2s), and we observed that MIR205HG expression was positively correlated with the number of ILC2s in patients with IPF. Collectively, these findings provide insights into the mechanisms by which basal cells contribute to IPF and suggest potential therapeutic targets.

关键词： venous ulcer   wound   chronic wound   healing   macrophage   RNA sequencing   IRF5  

摘要： Chronic wounds present a large burden to our healthcare system and are typically marked by a failure to transition out of the inflammatory phase of wound healing. Venous leg ulcers (VLUs) represent the largest portion of chronic wounds. A pilot study of eleven (11) patients with VLUs seen over a 12-week period was undertaken utilizing RNA sequencing of wound biopsies and plasma cytokine levels to determine if biomarkers could be identified that would distinguish between wounds which heal versus those that do not. Chronic wounds were found to have increased expression of genes relating to epithelial-to-mesenchymal transition (EMT), cartilage and bone formation, and regulation of apical junction. Plasma cytokine levels showed predictive potential for IL-15 and RANTES, which were found to increase over time in patients with healed wounds. Further research is needed to validate these biomarkers as well as additional study of other chronic wound models, such as diabetic foot ulcers (DFUs).

关键词： Inflammaging   Inflammatory factors   Keratinocytes   Human foreskin fibroblasts   IL-17 signal pathway   Rosa. roxburghii Tratt.  

摘要： Chronic inflammation is a critical mechanism contributing to the aging process;however, research specifically addressing chronic inflammation in skin biology remains limited. This study investigates the protective mechanism of Rosa roxburghii Tratt. (RRT) extract against UVB-induced inflammaging. RRT extract effectively reduces the secretion of IL-6, IL-1 alpha, TNF-alpha, and PGE2 in keratinocytes. Additionally, it attenuates UVB-induced IL-17 pathway activation by downregulating IL-17RA, c-Fos, and c-Jun protein levels, as well as the gene expression of IL-17RA, TRAF6, HSP90, and IKK gamma. Co-culturing human foreskin fibroblasts (HFF) with inflammatory factors secreted by UVB-exposed keratinocytes reveals that these factors significantly reduce mitochondrial membrane potential and mitochondrial reactive oxygen species (ROS), thereby promoting aging in HFF. The anti-inflammaging effects of RRT extract are achieved through the reduction of beta-galactosidase activity, targeting of the TGF-beta 1-Smad2/3 signaling pathway, upregulation of COL1A1 expression, and reduction of senescence-associated secretory phenotype secretion. This study provides a novel perspective and robust scientific foundation for exploring mechanisms of skin aging and potential therapeutic interventions.

关键词： Breast cancer   Combination therapy   Immunomodulation   Nanomedicine   Type II interferon  

摘要： Interferon-gamma (IFN-gamma) is a key mediator in antitumor immunity and immunotherapy responses, yet its clinical applications remain restricted to chronic granulomatous disease and malignant osteopetrosis. IFN-gamma effectiveness as a standalone treatment has shown limited success in clinical trials and its potential for synergistic effects when combined with immunotherapies is under clinical exploration. A particularly compelling combination is that of IFN-gamma with Toll-like receptor (TLR) agonists that holds significant promise for cancer treatment. Previously, we demonstrated chitosan (Ch)/poly(gamma-glutamic acid) (gamma-PGA) nanoparticles (NPs), known to activate TLRs, as adjuvants to radiotherapy by remodeling breast tumor microenvironment and systemic immunosuppression. These immunomodulatory abilities make Ch/gamma-PGA NPs promising adjuvants to IFN-gamma-based therapies. Here, we addressed the synergistic therapeutic potential of combining Ch/gamma-PGA NPs with IFN-gamma therapy in the 4T1 orthotopic breast tumor mouse model. While control animals (placebo-treated) had progressive tumor growth and lung metastases, those treated with either NPs or IFN-gamma alone had a significant slower tumor growth. Remarkably, primary tumor growth was halted throughout the duration of the treatment when both treatments were combined. Although the animals did not achieve durable complete responses upon treatment withdrawal, it was notable that the NPs plus IFN-gamma group presented a lower lung metastatic burden compared to other groups. Systemically, the combination therapy slightly attenuated immunosuppression and the percentage of splenic myeloid cells, while increased the percentage of T helper 1 cells and of cytotoxic T cells. Overall, this proof-ofconcept study suggests that Ch/gamma-PGA NPs potentiate IFN-gamma effects to reduce tumor progression, presenting a novel approach for anticancer strategies.

关键词： SARS-CoV-2   COVID-19   HLA   Italian bone marrow donor registry  

摘要： BackgroundSeveral studies suggest that the heterogeneous spread of SARS-CoV-2 pandemics started on December 2019 could be partially upheld by the prevalence of permissive class I HLA alleles in specific populations. Such HLA alleles are in fact unable to shape an efficient anti-viral immune-response in the hosts or sustain an exaggerated inflammatory T cell mediated response responsible for the COVID-19 disease. We previously reported an ecologic correlation between the risk of COVID-19 spreading across Italy and the germinal expression of permissive HLA-C*01 and -B*44 alleles in specific inter and intraregional populations along the first spreading *** that SARS-CoV-2 has undergone multiple adaptative mutations since the beginning of pandemics related to a natural immunization and to the worldwide campaign of anti-SARS-CoV-2 vaccination, we have carried out further analyses to evaluate whether the predictive value of class I HLA-allele gene prevalence and COVID-19 incidence has changed with time along the first four pandemics spreading waves in Italy. To this purpose we carried out an ecologic study followed by a case-control ***| Our data revealed that the direct correlation of HLA-C*01, and HLA-B*44 gene expression and COVID-19 risk was completely lost just after the first pandemics wave in Italy. On the contrary, the expression of HLA-B*49 allele in specific populations emerged as inversely correlated to the risk of COVID-19 and could be considered as a protective factor. The statistical significance of this correlation was progressively enforced in each subsequent spreading wave until February 2022. The following case-control study in the two Regions of Campania and Calabria in Italy confirmed the protective value of HLA-B*49 allele gene expression (OR = 0.289;p = 0.041), although statistical significance is lost after adjustment by logistic regression model. The analysis also detected multiple class I HLA-alleles whose expression

摘要： Pluripotent stem cells provide opportunities for treating injuries and previously incurable diseases. A major concern is the immunogenicity of stem cells and their progeny. Here, we have dissected the molecular mechanisms that allow natural killer (NK) cells to respond to human pluripotent stem cells, investigating a wide selection of activating and inhibitory NK-cell receptors and their ligands. Reporter cells expressing the activating receptor NKG2D responded strongly to embryonic stem (ES) cell lines and induced pluripotent stem (iPS) cell lines, whereas reporter cells expressing the activating receptors NKp30, NKp46, KIR2DS1, KIR2DS2, and KIR2DS4 did not respond. Human ES and iPS cells invariably expressed several ligands for NKG2D. Expression of HLA-C and HLA-E was lacking or low, insufficient to trigger reporter cells expressing the inhibitory receptors KIR2DL1, -2DL2, or -2DL3. Similar results were obtained for the pluripotent embryonic carcinoma cell lines NTERA-2 and 2102Ep, and also iPS-cell-derived neural progenitor cells. Importantly, neural progenitor cells and iPS-cell-derived motoneurons also expressed B7H6, the ligand for the activating receptor NKp30. In line with these observations, IL-2-stimulated NK cells showed robust cytotoxic responses to ES and iPS cells as well as to iPS-cell-derived motoneurons. No significant differences in cytotoxicity levels were observed between KIR/HLA matched and mismatched combinations of NK cells and pluripotent targets. Together, these data indicate that pluripotent stem cells and their neural progeny are targets for NK-cell killing both by failing to sufficiently express ligands for inhibitory receptors and by expression of ligands for activating receptors. © 2024 The Author(s). Published by Oxford University Press.