Quantitative glycoproteomics of high-density lipoproteins

In this work, we developed a targeted glycoproteomic method to monitor the site-specific glycoprofiles and quantities of the most abundant HDL-associated proteins using Orbitrap LC-MS for (glyco)peptide target discovery and QqQ LC-MS for quantitative analysis. We conducted a pilot study using the workflow to determine whether HDL protein glycoprofiles are altered in healthy human participants in response to dietary glycan supplementation.

The optimized HDL glycoproteomics method was sensitive enough to detect the effects of dietary supplements on HDL protein glycoprofiles even in a small sample size.     

Dasatinib and interferon alpha synergistically induce pyroptosis-like cell death in philadelphia chromosome positive acute lymphoblastic leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is a high-risk disease subtype with a dismal prognosis. Inhibiting BCR-ABL kinase alone is insufficient to eradicate Ph+ALL clones, and alternative BCR-ABL-dependent and -independent pathways need to be targeted as an effective strategy. Our study revealed that the combination of dasatinib and interferon-α showed synergistic activity against Ph+ALL, inducing mitochondrial dysfunction and causing necrosis-like cell lysis. Mechanistic studies showed that the induced cell death was caspase-3-independent. Canonical necroptosis signals, such as RIP1 and MLKL, were not activated; instead, the pyroptosis executor Gasdermin D was upregulated expression and activated. The expression levels of extracellular ATP and IL-1β were also upregulated, both of which are markers of pyroptotic cell death. In a murine Ph+ALL model, the dual drug treatment prolonged the survival of tumor-bearing mice. More importantly, we incorporated the dual drugs to maintenance therapy in 39 patients who were unfit for allogeneic stem cell transplantation (allo-HSCT). The median follow-up was 28.5 months, the 4-year disease-free survival and overall survival rates were 52.2% and 65.2%, respectively. Our data suggest that the combination of dasatinib and interferon-α has potential synergistic activity against Ph+ALL and shows promise as a maintenance therapy for Ph+ALL patients who are unfit for allo-HSCT.     

Association of body mass index with risk of prediabetes in Chinese adults: A population‐based cohort study

Aims/IntroductionOverweight and obesity in adults are strongly associated with an increased risk of prediabetes, and this study set out to gain a better understanding of the optimal body mass index (BMI) range for assessing the risk of prediabetes in the Chinese population.Materials and MethodsThe cohort study included 100,309 Chinese adults who underwent health screening. Participants were divided into six groups based on the cut‐off point for BMI recommended by the World Health Organization (underweight: <18.5 kg/m², normal‐weight: 18.5–24.9 kg/m², pre‐obese: 25.0–29.9 kg/m², obese class I: 30.0–34.9 kg/m², obese class II: 35.0–39.9 kg/m², and obese class III ≥40 kg/m²). The association of BMI with prediabetes and the shape of the correlation were modeled using multivariate Cox regression and restricted cubic spline regression, respectively.ResultsIn the multivariate Cox regression model, with normal weight as the control group, underweight people had a lower risk of developing prediabetes, whereas obese and pre‐obese people had a higher risk of prediabetes. Additionally, in the restricted cubic spline model, we found that the association of BMI with prediabetes follows a positive dose–response relationship, but does not conform to the pattern of obesity paradox. Among the general population in China, a BMI of 23.03 kg/m² might be a potential intervention threshold for prediabetes.ConclusionsThe national cohort study found that the association of BMI with prediabetes follows a positive dose–response relationship, rather than a pattern of obesity paradox. For Chinese people with normal weight, more attention should be paid to glucose metabolism when BMI exceeds 23.03 kg/m².     

Targeting tumor endothelial hyperglycolysis enhances immunotherapy through remodeling tumor microenvironment

Vascular abnormality is a hallmark of most solid tumors and facilitates immune evasion. Targeting the abnormal metabolism of tumor endothelial cells (TECs) may provide an opportunity to improve the outcome of immunotherapy. Here, in comparison to vascular endothelial cells from adjacent peritumoral tissues in patients with colorectal cancer (CRC), TECs presented enhanced glycolysis with higher glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Then an unbiased screening identified that osimertinib could modify the GAPDH and thus inhibit its activity in TECs. Low-dose osimertinib treatment caused tumor regression with vascular normalization and increased infiltration of immune effector cells in tumor, which was due to the reduced secretion of lactate from TECs by osimertinib through the inhibition of GAPDH. Moreover, osimertinib and anti-PD-1 blockade synergistically retarded tumor growth. This study provides a potential strategy to enhance immunotherapy by targeting the abnormal metabolism of TECs.     

轻中型颅脑损伤后认知功能障碍的DTI研究

目的应用弥散张量成像(diffusion tensor imaging,DTI)技术探讨轻中型颅脑损伤病人不同部位脑白质微结构改变与其认知功能障碍的相关性。方法分析127例轻中型颅脑损伤病人的临床资料,伤后10 d采用蒙特利尔认知评估量表(Mo CA)评定有无认知功能障碍,并常规行头颅MRI检查,采集DTI数据,测量两侧额叶、颞叶内侧、顶叶,胼胝体膝部和压部,中脑部位的感兴趣区各向异性分数(FA值)、表观弥散系数(ADC值),并与Mo CA评估结果进行相关性分析。结果以Mo CA量表为标准评定,无认知功能障碍41例(32.28%,无认知障碍组),存在认知功能障碍86例(67.72%,认知障碍组),主要表现为视空间与执行功能、注意力和计算力、语言、抽象能力、延迟记忆的障碍。与无认知障碍的病人相比,认知障碍的病人两侧额叶、颞叶内侧、胼胝体膝部FA值降低,ADC值增加,差异具有统计学意义(P0.01)。结论轻中型颅脑损伤病人早期存在显著认知功能障碍,以视空间与执行功能、注意力和计算力、语言、抽象能力、延迟记忆障碍为主。颅脑损伤后早期认知功能障碍与病人额叶、颞叶、胼胝体白质受损密切相关。     

H型血管铁死亡对骨质疏松性骨关节炎的影响及调节机制研究

随着全社会人口老龄化的加剧,绝经后女性罹患骨质疏松性骨关节炎的风险亦呈现高发趋势,严重危害中老年人的健康。研究证实血管形成及功能异常是加剧骨质疏松、骨关节炎病理退变的重要事件。H型血管(内皮细胞)在骨与软骨损伤修复中兼具成骨和成血管偶联功能,其形态与功能异常将影响骨质疏松、骨关节炎的损伤修复。铁死亡作为近年来发现的一种新型细胞死亡模式,其主要由铁依赖性脂质过氧化和活性氧诱导损伤引起细胞膜断裂,线粒体变小等改变。而H型血管铁死亡对骨质疏松性骨关节炎病程的影响途径及调节机制尚需进一步探讨,旨在为今后以H型血管铁死亡为切入点进而防治骨质疏松性骨关节炎开辟新方向。     

基于知识图谱的糖尿病治疗领域的可视化分析

目的探讨可视化软件CiteSpace在国际糖尿病治疗研究领域的应用。方法运用CiteSpace软件和SCI—E数据库本身功能进行研究。结果通过对文献数量、研究力量、关键词、引文和主要出版物的分析,识别学科的研究前沿和热点。结论国际关于糖尿病治疗领域的研究呈上升趋势,提出了该领域研究的发展趋势、科技政策导向。