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.     

非酒精性脂肪性肝炎患者肝脏受控衰减参数的变化

目的 探讨瞬时弹性记录仪(FibroScan)检测肝脏受控衰减参数(CAP)诊断非酒精性脂肪性肝炎(NASH)的效能.方法 2016年1月～2020年1月我院收治的NASH患者142例和同期健康体检者130例,使用FibroScan检测肝脏CAP值.采用受试者工作特征曲线(ROC)并计算曲线下面积(AUC)评价CAP值...     

Association between clustering of cardiovascular risk factors and resting heart rate in Chinese population: a cross-sectional study

BACKGROUNDEpidemiologic studies have explored the association between a single cardiovascular risk factor (CVRF) and resting heart rate (RHR), but the research on the relation of multiple risk factors with RHR remains scarce. This study aimed to explore the associations between CVRFs clustering and the risk of elevated RHR.METHODSIn this cross-sectional study, adults aged 35–75 years from 31 provinces were recruited by the China PEACE Million Persons Projects from September 2015 to August 2020. We focused on seven risk factors: hypertension, diabetes mellitus, dyslipidemia, obesity, smoking, alcohol use, and low physical activity. Multivariate logistic regression was used to calculate odds ratios (OR) for elevated RHR (> 80 beats/min).RESULTSAmong 1,045,405 participants, the mean age was 55.67 ± 9.86 years, and 60.4% of participants were women. The OR (95% CI) for elevated RHR for the groups with 1, 2, 3, 4 and ≥ 5 risk factor were 1.11 (1.08–1.13), 1.36 (1.33–1.39), 1.68 (1.64–1.72), 2.01 (1.96–2.07) and 2.58 (2.50–2.67), respectively (P_trend < 0.001). The association between the CVRFs clustering number and elevated RHR was much more pronounced in young males than in other age-sex subgroups. Clusters comprising more metabolic risk factors were associated with a higher risk of elevated RHR than those comprising more behavioral risk factors. CONCLUSIONSThere was a significant positive association between the CVRFs clustering number and the risk of elevated RHR, particularly in young males. Compared clusters comprising more behavioral risk factors, clusters comprising more metabolic risk factors were associated with a higher risk of elevated RHR. RHR may serve as an indicator of the cumulative effect of multiple risk factors.

Over the past several years, the rapid development of smart wrist-worn devices has resulted in a convenient approach to monitoring resting heart rate (RHR) in daily life. RHR is becoming a promising indicator of cardiovascular health. Observational studies have shown that elevated RHR is associated with increased all-cause and cardiovascular mortality in populations with or without cardiovascular disease (CVD).^[1,2] Elevated RHR has also been found to be associated with cardiovascular risk factors (CVRFs), such as hypertension, diabetes mellitus, dyslipidemia, low physical activity and smoking, indicating its potential to reflect total cardiac risk.^[3–7] There is abundant epidemiologic evidence supporting the association between a single CVRF and RHR, but studies exploring associations between multiple CVRFs and RHR are limited. CVRFs tend to cluster within individuals, and several weak risk factors combined may result in a much higher risk than that due to a single strong risk factor. According to a cross-sectional survey in China, more than 45% of Chinese adults have two or more coexisting CVRFs.^[8] Thus, it is important to consider the situation of multiple CVRFs clustering. However, very few studies have analyzed the association between CVRFs clustering and RHR, and several aspects remain unknown. Firstly, prior studies mainly focused on the relation between metabolic risk factors and RHR.^[9–11] Behavioral risk factors such as smoking, physical activity and alcohol use have rarely been considered, even though these risk factors also have a significant effect on heart rate.^[3,5,7] Secondly, most studies merely dealt with the relation of CVRFs clustering number with RHR, while regarding each number of risk factors, different combinations of risk factors have not yet been considered before.^[9,12] It is important to consider different CVRF clustering patterns since some risk factors combined may lead to a higher risk of elevated RHR than others, even if the number of CVRFs is the same. Thirdly, prior studies did not assess associations stratified by sex and age. It has been well documented that RHR levels differ by sex and age. The RHR in women was on average 2–7 beats/min higher than that in men, and there was a decrease in the RHR with age.^[13,14] As such, whether the associations of CVRFs clustering with RHR varied between sex and age remains unclear. Taking advantage of the large sample size in our study, we are able to include a wider range of CVRFs (metabolic and behavioral risk factors), comprehensively evaluate the association between these CVRFs clustering and RHR, and further explore sex and age differences. This finding may inform us whether RHR can be used as a simple and efficient metric for the identification of high-risk individuals who require more intensive risk factor evaluation and earlier cardiovascular health monitoring in resource-constrained countries with substantial CVD burdens, such as China. To bridge this knowledge gap, we used data from the China PEACE Million Persons Projects, a nationwide screening project, to explore (1) the association between the number of CVRFs clustering and elevated RHR in the overall population and populations stratified by age and sex; and (2) the associations between different CVRFs clusters and the risk of elevated RHR in the overall population and populations stratified by sex.     

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.     

工作繁荣在教练型领导与护士职业成长间的中介效应

目的 探讨护士工作繁荣对教练型领导与职业成长关系的中介效应。方法 采用多阶段分层抽样法,选择河南省7所三级甲等医院的447名护士为研究对象,使用护士职业成长量表、教练型领导感知评价量表(护士他评版)和工作繁荣量表进行调查。结果 护士评估的教练型领导评分为69.61±19.17,工作繁荣评分为49.93±10.12,职业成长评分为49.00±10.07,三者之间互为正相关(均P<0.05)。分层回归分析结果显示,在控制一般资料变量后,教练型领导及工作繁荣能解释职业成长总变异的38.2%。工作繁荣在教练型领导与职业成长之间起中介作用,中介效应占总效应的52.560%。结论 教练型领导有助于提升临床护士工作繁荣水平,进而促进其职业成长,提示护理管理者施展教练型领导以挖掘护士职业发展潜力。     

Idiopathic Membranous Nephropathy with Solitary Immunoglobulin A Deposition: A Case Report and a Review of the Literature

A 63-year-old man with an 8-year history of proteinuria was diagnosed with nephrotic syndrome, and a renal biopsy was performed. Light and electron microscopic analyses showed classic features of idiopathic membranous nephropathy (IMN). However, immunofluorescence tests revealed solitary polyclonal granular IgA deposition along the glomerular capillary walls, rather than IgG, which is often dominant in IMN. The combined use of corticosteroids and calcineurin inhibitor was noticeably effective in reducing proteinuria and improving edema in the current case. Two additional rare cases of IMN with solitary IgA deposition were reviewed, and long-term surveillance is still warranted to characterize its clinicopathological features and outcome.     

Exosomes Derived from Glioma Cells under Hypoxia Promote Angiogenesis through Up-regulated Exosomal Connexin 43

Glioblastoma multiform (GBM) is a highly aggressive primary brain tumor. Exosomes derived from glioma cells under a hypoxic microenvironment play an important role in tumor biology including metastasis, angiogenesis and chemoresistance. However, the underlying mechanisms remain to be elucidated. In this study, we aimed to explore the role of connexin 43 on exosomal uptake and angiogenesis in glioma under hypoxia. U251 cells were exposed to 3% oxygen to achieve hypoxia, and the expression levels of HIF-1α and Cx43, involved in the colony formation and proliferation of cells were assessed. Exosomes were isolated by differential velocity centrifugation from U251 cells under normoxia and hypoxia (Nor-Exos and Hypo-Exos), respectively. Immunofluorescence staining, along with assays for CCK-8, tube formation and wound healing along with a transwell assay were conducted to profile exosomal uptake, proliferation, tube formation, migration and invasion of HUVECs, respectively. Our results revealed that Hypoxia significantly up-regulated the expression of HIF-1α in U251 cells as well as promoting proliferation and colony number. Hypoxia also increased the level of Cx43 in U251 cells and in the exosomes secreted. The uptake of Dio-stained Hypo-Exos by HUVECs was greater than that of Nor-Exos, and inhibition of Cx43 by ^37,43gap27 or lenti-Cx43-shRNA efficiently prevented the uptake of Hypo-Exos by recipient endothelial cells. In addition, the proliferation and total loops of HUVECs were remarkably increased at 24 h, 48 h, and 10 h after Hypo-Exos, respectively. Notably, ^37,43gap27, a specific Cx-mimetic peptide blocker of Cx37 and Cx43, efficiently alleviated Hypo-Exos-induced proliferation and tube formation by HUVECs. Finally, ^37,43gap27 also significantly attenuated Hypo-Exos-induced migration and invasion of HUVECs. These findings demonstrate that exosomal Cx43 contributes to glioma angiogenesis mediated by Hypo-Exos, and suggests that exosomal Cx43 might serve as a potential therapeutic target for glioblastoma.     

Effects of In-Process Ultrasonic Vibration on Weld Formation and Grain Size of Wire and Arc Additive Manufactured Parts

Wire and arc additive manufacturing (WAAM) is a competitive technique, which enables the fabrication of medium and large metallic components. However, due to the presence of coarse columnar grains in the additively manufactured parts, the resultant mechanical properties will be reduced, which limits the application of WAAM processes in the engineering fields. Grain refinement and improved mechanical properties can be achieved by introducing ultrasonic vibration. Herein, we applied ultrasonic vibration to the WAAM process and investigated the effects of wire feed speed, welding speed, and ultrasonic amplitude on the weld formation and grain size during ultrasonic vibration. Finally, a regression model between the average grain size and wire feed speed, welding speed, and ultrasonic amplitude was established. The results showed that due to the difference in heat input and cladding amount, wire feed speed, welding speed, and ultrasonic amplitude have a significant influence on the weld width and reinforcement. Excessive ultrasonic amplitude could cause the weld to crack during spreading. The average grain size increased with increasing wire feed speed and decreasing welding speed. With increasing ultrasonic amplitude, the average grain size exhibited a trend of decreasing first and then increasing. This would be helpful to manufacture parts of the required grain size in ultrasonic vibration-assisted WAAM fields.     

Transport Property and Spin–Orbit Torque in 2D Rashba Ferromagnetic Electron Gas

In this paper, we investigate the spin–orbit torque and transport property in a 2D Rashba ferromagnetic electron gas. The longitudinal conductivity can be divided into two parts: the first term is determined by the charge density and is independent of the spin degrees of freedom. The second term depends on the two bands that spin in the opposite directions, and it is directly proportional to spin–orbit torque regardless of the band structure and temperature. This is a general and underlying relation between the transport property and spin–orbit torque. Moreover, we show the impacts of the spin–orbit coupling constant and Fermi energy on transverse conductivity and spin–orbit torque, which is helpful for relevant experiments.     

民国时期上海主要中医药团体简介

在评价近代上海的中医活动及其影响时,中医团体的地位不容忽视。上海是我国最先创办中医团体的地区。在20世纪前半叶的近50年中,上海的中医团体活动十分活跃,具有创办时间早,组织规模大,团体数量多,活动影响广等特点,其辐射出的作用和影响在近代我国的中医发展史中也扮演着十分重要的角色。