Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles

Background Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10⁻⁶). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma     

葛根素对家兔肢体缺血再灌注后心脏功能的保护作用

目的:观察葛根素对家兔肢体缺血再灌注所致心脏损伤的保护作用并探讨其机制.方法:家兔40只,随机分4组:Ⅰ组为假手术对照组、Ⅱ组为缺血再灌注组、Ⅲ组为葛根素低剂量治疗组、Ⅳ组为葛根素高剂量治疗组.免疫组化法检测心肌组织Bcl-2和Bax蛋白表达;原位缺口末端标记法(TUNEL)检测心肌细胞凋亡;比色法测定心肌组织超氧化物岐化酶(SOD)和髓过氧化物酶(MPO)活性,丙二醛(MDA)含量,测定血清乳酸脱氢酶(LDH)活性;通过生理记录仪观察心功能指标.结果:与Ⅱ组比较,Ⅲ、Ⅳ组左心室功能增强,且Ⅳ组的左心室收缩功能比Ⅲ组增强,同时,Ⅲ、Ⅳ组心肌组织MDA含量和血清LDH活性减少,Bax蛋白表达减少,Ⅳ组的心肌凋亡指数低于Ⅱ组,心肌Bcl-2表达高于Ⅱ组.结论:葛根素促进肢体缺血再灌注后心脏功能的恢复,表现为剂量依赖效应,其作用机制与抗氧化损伤和抗细胞凋亡有关.     

聚偏氟乙烯支撑液膜萃取乳酸

采用聚偏氟乙烯固体微孔膜,与溶解在煤油中的三烷基氧磷组成支撑液膜(SLM),分离稀水溶液中的乳酸。考察了pH值、料液浓度、载体浓度、温度、料液及解析液流量对传质速率的影响。同时进行了膜稳定性的定性研究。发现乳酸以分子形式通过SLM;载体浓度为40%时传质速率最大;SLM对乳酸的通量与稀水溶液中乳酸浓度成正比。料液和解析液预先用有机相饱和时,膜的稳定性可大大改善。     

Inhaled lodoxamide tromethamine in the treatment of perennial asthma: a double-blind placebo-controlled study

The efficacy of lodoxamide tromethamine in the treatment of asthma was studied in a 16-week double-blind, placebo-controlled study of 68 perennial allergic subjects with asthma. Patients received either lodoxamide tromethamine, 0.25 mg four times daily, or placebo, administered by metered-dose inhaler. Response to treatment was assessed by analyzing changes in asthma symptoms, inhaled bronchodilator requirements, and pulmonary function when compared to a 2-week baseline period. Patients treated with lodoxamide tromethamine demonstrated an improvement in daytime breathing difficulty, cough, sputum production, and sleep (p less than 0.01 to 0.05), but improvement was not significantly different from that demonstrated by placebo-treated patients. Patients from both treatment groups were able to reduce their inhaled bronchodilators (p less than 0.01), but again no significant difference was apparent between lodoxamide tromethamine and placebo treatment, nor were there any differences in peak expiratory flow rate or FEV1 between the two groups. Seven patients who received lodoxamide tromethamine withdrew because of a sensation of heat and gastrointestinal symptoms. Thus, although lodoxamide tromethamine possesses potent mast cell-stabilizing activity in vitro, we have failed to demonstrate any useful long-term effect in the treatment of mild allergic asthma.     

Systemic embolism in chronic sinoatrial disorder.

We attempted to estimate the prevalence of systemic embolism in patients with chronic sino-atrial disorder. In a group of 100 patients, evidence of embolism was found in 16, of whom 15 had the bradycardia-tachycardia syndrome. In 712 controls with chronic complete heart block, who were matched for age and sex, embolism had occurred in only 1.3 per cent (P less than 0.001). A second group of 41 patients with chronic ventricular bradycardia and atrial flutter or fibrillation had an embolic prevalence of 7.3 per cent, which was also greater than that in the controls (P less than 0.05). All patients with sinoatrial disorder in whom systemic embolism developed were over 54 years of age; multiple episodes occurred in six. The risk of embolization remains even if the bradycardia-tachycardia syndrome is replaced by stable atrial fibrillation. Impaired atrial function appears to be a key factor in predisposing to intracardiac thrombosis, and paroxysmal supraventricular tachycardia increases the risk of subsequent embolization.     

人类ZAKβ与YWHAZ蛋白相互作用的初步研究

目的研究ZAKβ与YWHAZ蛋白之间的相互作用。方法以ZAKβ为诱饵蛋白,利用酵母双杂交筛选人类肝脏cDNA文库,经GST Pull-down、免疫共沉淀和细胞共定位实验分别验证ZAKβ与猎物蛋白在体外和细胞内的相互作用,构建ZAKβ的截短体以确定相互作用的区域,用磷酸化抗体检测ZAKβ在相互作用中的磷酸化作用,并通过流式细胞仪检测这对蛋白相互作用对细胞周期的影响。结果利用酵母双杂交筛选到一个能与ZAKβ相互作用的蛋白YWHAZ,并在体外和细胞内都验证了这二者的相互作用,发现这两个蛋白都能共定位于293T细胞的胞质中,确定了ZAKβ的N端1~250氨基酸为与YWHAZ蛋白相互作用的区域。体外实验发现了这二者的相互作用涉及到磷酸化反应,发现这对蛋白的相互作用能提高293T细胞的G2期水平。结论首次发现并证实了ZAKβ和YWHAZ之间的相互作用,发现该相互作用涉及到磷酸化过程并能够对细胞周期产生影响。     

Cloning and characterization of a novel gene which encodes a protein interacting with the mitosis-associated kinase-like protein NTKL

NTKL is an evolutionarily conserved kinase-like protein. The cell-cycle-dependent centrosomal localization of NTKL suggested that it was involved in centrosome-related cellular function. The mouse NTKL protein is highly homologous with human NTKL. A novel mouse protein was identified as an NTKL-binding protein (NTKL-BP1) by yeast two-hybrid screening, and the full-length cDNA was amplified based on the result of a sequence data analysis cloning strategy. The full-length cDNA sequence of the NTKL-BP1 gene consists of 2,537 bp, which encode 368 amino acids. A database search revealed that homologues of NTKL-BP1 exist in different organisms, including Arabidopsis thaliana, Drosophila melanogaster, Plasmodium falciparum, Geobacter metallireducens, Anopheles gambiae and human. It suggests that NTKL-BP1 is an evolutionarily conserved protein. The expression of NTKL-BP1 was observed in multiple normal mouse tissues. The interaction of the two proteins was confirmed by co-immunoprecipitation. Moreover, immunofluorescent staining indicated that NTKL and NTKL-BP1 were all localized in the cytoplasm.     

非侵入式眼表分析仪评价儿童异常瞬目症与干眼的相关性

目的：通过裂隙灯显微镜和非侵入式眼表分析仪评价异常瞬目患儿干眼的状况。方法：系列病例研 究。选取2017-2018年于南京医科大学附属眼科医院门诊收治的85例（170眼）3～13岁眼表正常的 异常瞬目患儿。采用裂隙灯显微镜行眼前节检查、Keratograph-D眼表综合分析仪测量非侵入性泪河 高度（NTMH）、非侵入性首次泪膜破裂时间（NITBUTf）、非侵入性平均泪膜破裂时间（NITBUTav）、 睑板腺缺失评分等分析儿童异常瞬目的原因。数据采用t检验、单因素方差分析、秩相关进行分析。 结果：85例患者NTMH值为（0.19±0.05）mm;NITBUTf值为（7.5±5.3）s;NITBUTav值为（8.6±5.6） s;睑板腺缺失面积评分为（0.7±0.8）分。睑板腺拍照中78眼睑板腺均无缺失,62眼睑板腺缺失面积 <1/3,27眼睑板腺缺失面积为1/3～2/3,3眼睑板腺缺失面积>2/3。46眼伴睑板腺腺体形态异常。77 例（91%）被诊断为干眼,8例（9%）正常。其中水液缺乏型干眼占10例（13%）;蒸发过强型干眼占 25例（32%）;混合型干眼占42例（55%）。性别与NTMH无相关性,但与NITBUTf和NITBUTav均有 显著相关性（r=0.31、0.32,P<0.001）。年龄与NTMH和NITBUTf无明显相关性,但与NITBUTav有 相关性（r=0.19,P<0.017）。异常瞬目的病程与NTMH、NITBUTf和NITBUTav均呈显著负相关（r=- 0.61、-0.37、-0.40,P<0.001）。结论：干眼可能是导致眼表正常的儿童异常瞬目的主要原因,非侵入 式眼表综合分析仪是一种非接触、无创、可重复性强的快速检查手段,在异常瞬目患儿眼表状况评 估中具有很高的应用价值。     

基于中医临床证候探讨新型冠状病毒肺炎在岭南地区的疫性特点

目的:通过分析广东省第二人民医院收治的新型冠状病毒肺炎(以下简称新冠肺炎)患者的临床资料,从中医临床证候探讨该病在岭南地区的疫性特点,更好地指导临床辨证治疗。方法:收集广东省第二人民医院收治的36例新冠肺炎患者的临床资料,其中输入病例20例,本地病例16例,分析全部病例、输入病例和本地病例的临床资料和证候特点。结果:新冠肺炎患者年龄分布较广,平均年龄45岁,以男性居多,55.56%的患者为外地输入病例,44.44%的患者为本地感染病例。全部病例证型以湿邪郁肺型和邪热壅肺型为主,分别占44.44%和38.89%;91.67%的患者呈现“湿”的病理特点,72.22%的患者呈现“热”的病理特点。其中输入病例证型以湿邪郁肺型为主,占65.00%,100%的患者呈现“湿”的病理特点,55.00%呈现“热”的病理特点;本地病例证型以邪热壅肺为主,占56.25%,93.75%的患者呈现“热”的病理特点,81.25%呈现“湿”的病理特点。结论:本次疫病在岭南地区的疫性属于以湿邪和热邪为主导的“湿热疫”,病机特点为湿热并重;输入性病例多表现为以湿邪为患的“湿疫”,有化热的趋势和倾向,病机特点为湿重于热;本地病例多表现为以热邪为主的“温热疫”,病机特点为热重于湿。此次新冠肺炎不同地区存在不同疫性的可能,辨证和治疗要遵守三因制宜的原则。     

PEWS联合分级护理模式在急诊高热惊厥患儿中的应用观察

目的　分析儿童早期预警评分（PEWS）联合分级护理模式在急诊高热惊厥患儿中的应用效果。方法　选取2020年5月至2021年7月汝州市人民医院收治的高热惊厥患儿126例为研究对象，按护理方式不同分为参照组和研究组，各63例。参照组男40例、女23例，年龄（30.06±4.32）个月，给予常规急诊护理；研究组男42例、女21例，年龄（29.48±4.28）个月，在参照组基础上给予PEWS联合分级护理。对比两组护理效果、急救情况、并发症及家属护理满意度。计量资料采用t检验，计数资料采用χ²检验，等级资料采用U检验。结果　研究组护理总有效率为98.41%（62/63），高于参照组87.30%（55/63），差异有统计学意义（χ²=5.863，P=0.016）。研究组住院时间、急救时间、体温恢复时间、惊厥消失时间分别为（4.32±1.05）d、（32.18±5.26）min、（1.87±0.42）d、（4.12±1.02）min，均短于参照组的（5.14±1.08）d、（43.25±5.14）min、（2.38±0.48）d、（5.84±1.04）min，差异均有统计学意义（均P<0.05）。研究组并发症发生率为3.17%（2/63），低于参照组14.29%（9/63），差异有统计学意义（χ²=6.952，P=0.008）。研究组常规护理、预检分诊、基础指导、健康宣教评分分别为（19.79±3.84）分、（20.84±3.08）分、（20.55±3.16）分、（21.27±2.85）分，均高于参照组的（16.28±3.57）分、（17.12±3.14）分、（16.39±3.22）分、（18.16±2.76）分，差异均有统计学意义（均P<0.05）。结论　应用PEWS联合分级护理模式应用于急诊高热惊厥患儿，能促进患儿恢复，缩短急救时间与住院时间，降低并发症发生风险，提高家属护理满意度。