The progress and confusion of anti-PD1/PD-L1 immunotherapy for patients with advanced non-small cell lung cancer

Recently, immunotherapy has evolved into a true treatment modality with the approval of PD-1 and PD-L1 inhibitors as the standard care for first-line treatment in patients with non-small cell lung cancer (NSCLC). Until now, for patients with advanced NSCLC, treatment of targeting immune checkpoints reveals a promising survival benefit, and some patients even get long term survive, which creates a paradigm shift in NSCLC treatment. However, many issues or problems are also appearing in clinical practice, such as the lower overall efficacy rate (20–40%), treatment modes, populations choice of immunotherapy, drug resistance, and safety, etc. Thus, in this review, we will mainly summarize and discuss the recent development and confusion of PD-1/PD-L1 inhibitors for advanced NSCLC patients based on current clinical studies.     

Low dose naltrexone (LDN) enhances maturation of bone marrow dendritic cells (BMDCs)

It has been demonstrated previously that immune cell activation and proliferation were sensitive to the effects of naltrexone, a non-peptidic δ-opioid receptor selective antagonist and opioid receptors on BMDCs have been detected [1]. However, there is little prior data published on naltrexone and DCs. Therefore, we hypothesized that LDN could exert modulating effect on BMDCs. In present study, we studied influence of LDN on both phenotypic and functional maturation of BMDCs. Changes of BMDC post-treatment with LDN were evaluated using conventional light microscope and transmission electron microscopy (TEM); flow cytometry(FCM); cytochemistry; acid phosphatase activity(ACP) test; FITC-dextran bio-assay; mixed lymphocytes and enzyme-linked immunosorbent assay (ELISA). We have found that LDN enhances maturation of BMDCs as evidenced by 1) up-regulating the expression of MHC II, CD40, CD83, CD80 and CD86 molecules on BMDCs; 2) down-regulating the rates of pinocytosis and phagocytosis accompanied by the results of decreased ACP, and FITC-dextran bio-assay; 3) mounting potential of BMDCs to drive T cell; and 4) inducing secretion of higher levels of IL-12 and TNF-α. It is therefore concluded that LDN can efficiently promote the maturation of BMDCs via precise modulation inside and outside BMDCs. Our study has provided meaningful mode of action on the role of LDN in immunoregulation, and rationale on future application of LDN for enhancing host immunity in cancer therapy and potent use in the design of DC-based vaccines for a number of diseases.     

褪黑素对锰致小鼠纹状体多巴胺能系统障碍的影响

目的研究锰对小鼠纹状体多巴胺系统的影响以及褪黑素(MLT)的干预作用,为锰中毒机制的研究提供理论依据。方法小鼠70只,随机均分为(1)对照组、(2)氯化锰组、(3)低MLT+氯化锰组、(4)中MLT+氯化锰组、(5)高MLT+氯化锰组。第1、2组皮下注射(sc)0.9%氯化钠,第3~5组sc给予1.25、2.5和5 mg/kg MLT;2 h后,第1组腹腔注射(ip)0.9%生理盐水,第2~5组ip给予50 mg/kg Mn Cl2。每天1次,连续2周。ELISA检测黑质内多巴胺(DA)含量,免疫组织化学及western blotting检测DAT和DRD1的蛋白水平。结果与对照组相比,氯化锰组上述指标均出现了不同程度的降低,纹状体DA含量显著降低69.97%(P0.01),免疫组织化学结果显示DAT和DRD1积分光密度分别下降62.54%和66.61%(P0.01),DAT和DRD1的蛋白水平均明显降低;与氯化锰组相比,随着MLT浓度的升高,DA含量、DAT和DRD1表达量逐渐上升,并呈剂量-效应关系。结论过量锰暴露可导致纹状体多巴胺系统的损伤,褪黑素可以拮抗锰所致的上述变化。     

贝伐珠单抗联合伊立替康与雷替曲塞治疗氟尿嘧啶耐药晚期结直肠癌的疗效和安全性

目的 观察贝伐珠单抗联合伊立替康与雷替曲塞方案在氟尿嘧啶类药物耐药后的晚期结直肠癌患者中的疗效及安全性。方法 收集中国医科大学附属第一医院2014—2019年收治的氟尿嘧啶类耐药的60例晚期结直肠癌患者,对照组30例,应用伊立替康联合雷替曲塞方案（IR）;实验组30例,应用IR联合贝伐珠单抗方案。分析比较两组患者的客观有效率（ORR）、疾病控制率（DCR）、无进展生存时间（PFS）及不良反应发生情况。结果 实验组和对照组ORR分别为6.67%和3.33%,DCR分别为66.67%和53.33%,两组ORR和DCR比较差异无统计学意义。实验组和对照组中位PFS分别为6.0个月和3.1个月,差异有统计学意义（P=0.020 4）。两组不良反应以Ⅰ/Ⅱ级多见,Ⅲ/Ⅳ级不良反应发生率低,实验组蛋白尿的发生率高于对照组,差异有统计学意义（P=0.001）。其余如出血、转氨酶升高、恶心、呕吐、腹泻、发热、皮疹、高血压等不良反应发生率均为实验组高于对照组,但差异无统计学意义。结论 贝伐珠单抗联合伊立替康与雷替曲塞方案可提高既往氟尿嘧啶类治疗耐药后的晚期结直肠癌患者的疗效,无进展生存期增加,不良反应可耐受,值得进一步研究。     

Prediction of Upper Limb use Three Months after Stroke: A Prospective Longitudinal Study

BackgroundA major goal of upper limb (UL) rehabilitation after stroke is to facilitate the use of the paretic arm in daily life activities.PurposeTo examine if UL impairment two weeks after stroke can predict real-life UL use at three months. Furthermore, to identify additional factors which contribute to future UL use, and characteristics of patients who do not achieve normal UL use.MethodsThis study included patients with stroke ≥ 18 years. UL impairment was assessed by Fugl-Meyer upper extremity motor assessment (FM). Use ratio between affected and unaffected UL was assessed with accelerometers at three months after stroke. The association between FM score and UL use ratio was investigated with linear regression models and adjusted for secondary variables. Non-normal use was examined by a logistic regression.ResultsEighty-seven patients were included. FM score two weeks after stroke predicted 38% of the variance in UL use ratio three months after stroke. A multivariate regression model predicted 55%, and the significant predictors were FM, motor-evoked potential (MEP) status, and neglect. Non-normal use could be predicted with a high accuracy based on MEP and/or neglect. In a logistic regression sensitivity for prediction of non-normal use was 0.93 and specificity was 0.75.ConclusionBetter baseline capacity of the paretic UL predicted increased use of the arm and hand in daily life. Non-normal UL use could be predicted reliably based on the absence of MEPs and/or presence of neglect.     

三阴性乳腺癌的治疗研究进展

［摘要］　　三阴性乳腺癌(TNBC)是一类强异质性的乳腺恶性肿瘤,具有不同于其他类型乳腺癌的独特生物学特征及病理学特征,其雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体-2(HER-2)的免疫组化标记均为阴性。由于其缺乏相应的激素受体和HER-2表达,TNBC早期和术后的主要治疗方法为含蒽环类和紫杉类药物的新辅助化疗,但对于已发生复发或转移的患者仍缺乏有效的治疗方案,故TNBC的治疗仍是医学界的难题。该文对TNBC的治疗研究进展作一综述。     

AuNP and ssDNA capped mesoporous silica nanoparticles for laser controlled drug release

In order to improve drug efficacy, and reduce drug toxicity and side effects, a novel drug controlled release system was developed based on mesoporous silica nanoparticles (MSNs) with gold nanoparticles (AuNPs) acting as pore caps and short single-stranded DNA (ssDNA) oligomers as the linker. The synthesised composites were characterized by Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (XRD), thermogravimetric analysis (TGA), zeta potential measurement, transmission electron microscopy (TEM) and UV-vis spectroscopy. The anticancer drug doxorubicin (Dox) was applied as a model drug to investigate the 808 nm near infrared (NIR) laser-controlled drug release behavior at different pH by fluorescence measurements. The investigation results demonstrate that this nanocarrier could achieve drug controlled release by external near-infrared (NIR) laser stimulation, which is expected to be applied in cancer therapy.

Gold nanoparticles were linked to the surface of mesoporous silica through a polyA oligonucleotide and infrared stimulation controlled drug release.     

新疆城市社区卫生服务机构“2+X”家庭医生团队预测及运行研究

背景　家庭医生团队作为签约服务的提供主体,基于目前的人力资源现状,如何科学地组建家庭医生团队是进一步推广家庭医生签约服务的关键。目的　预测“2+X”家庭医生团队发展情况,探索新疆城市社区卫生服务机构家庭医生签约服务运行情况,为加快推进家庭医生签约服务提供科学依据。方法　2011—2017年新疆城镇人口、城市社区卫生服务机构执业（助理）医师及注册护士数据来源于2012—2018年《新疆统计年鉴》。2018年新疆城镇人口数来源于新疆维吾尔自治区2018年国民经济和社会发展统计公报。本研究于2019年进行,依据2011—2017年上述数据,采用灰色预测模型GM（1,1）,预估2019—2025年新疆城镇人口数及2018—2025年家庭医生团队相关卫生技术（卫技）人员数。计算2011—2025年新疆城市社区卫生服务机构“2+X”家庭医生团队数量情况。观察每3 000服务人口的标准下和每2 000服务人口的标准下,家庭医生团队服务人口数及“2+X”家庭医生团队服务人口覆盖率。结果　预测2019—2025年新疆城镇人口数逐年增长,从2019年1 317.39万人增至2025年1 706.42万人;执业（助理）医师数逐年增长,由2019年的3 083人增至2025年3 268人;注册护士数逐年增长,由2019年3 256人增至2025年3 940人。以“2+X”家庭医生团队模式最低配置标准组建家庭医生团队,预测2018—2025年“2+X”家庭医生团队数量逐渐增多,且2025年理论上新疆城市社区卫生服务机构卫技人员能够组建3 268个团队。2011—2016年注册护士数低于职业（助理）医师数,直到2017年有所改善,医师与护士比达1∶1.02,并一直保持上升趋势,但增长趋势较慢,预测2020年可达1∶1.08,2025年可达1∶1.21。由灰色模型GM（1,1）的预测结果可知,2011—2025年新疆城镇人口数总体呈上升趋势。以每3 000服务人口数的家庭医生团队服务标准,“2+X”家庭医生团队服务人口覆盖率均在70%以上,最高达到82%;以每2 000服务人口数的家庭医生团队服务标准,2018年“2+X”家庭医生团队服务人口覆盖率为48%,理论上到2025年,“2+X”家庭医生团队服务人口覆盖率为38%。结论　2018—2025年“2+X”家庭医生团队数量逐渐增多,但依据每个家庭医生团队服务2 000人口的标准,未来新疆城市社区卫生服务机构医护需求量很大,距实现辖区服务人口全覆盖目标仍有一定的距离,需加强家庭医生团队人才培养,组建提高型家庭医生团队,实现“家家拥有家庭医生,人人享有基本医疗卫生服务”。     

钙调蛋白及其突变体与电压门控钠离子通道1.2异亮氨酸-谷氨酰胺基序的结合作用

目的: 探讨在不同钙离子浓度下电压门控钠离子通道（Na_V）1.2与钙调蛋白（CaM）的结合,并分析CaM的钙离子结合位点突变后与Na_V1.2结合能力的变化。方法: 应用PCR技术构建Na_V1.2蛋白片段异亮氨酸-谷胺酰胺（IQ）基序的cDNA,采用QIAGEN点突变技术构建CaM突变体（CaM₁₂、CaM₃₄、CaM₁₂₃₄）,应用牵出（pull-down）试验技术检测有钙（100 nmol/L钙离子浓度）和无钙条件下Na_V1.2 IQ与CaM及其突变体（CaM₁₂、CaM₃₄、CaM₁₂₃₄）的结合情况。结果: CaM与Na_V1.2 IQ在无钙和有钙情况下均可互相结合,而单独重组谷胱甘肽-S-转移酶（GST）不具有与CaM结合的能力。无钙条件下CaM与Na_V1.2 IQ的结合量大于有钙条件下两者的结合量（P < 0.05）;无钙条件下,CaM野生型与Na_V1.2 IQ结合量大于CaM突变体与Na_V1.2 IQ的结合量,其中CaM₁₂₃₄的结合能力在三个突变体中最弱（P < 0.05）。结论: CaM及其突变体对Na_V1.2 IQ的结合具有钙离子依赖性,这一CaM调控Na_V1.2新机制为离子通道疾病研究提供了一定依据。     

基于引文出版年光谱的SARS研究起源与演化

以Web of Science数据库中收录的SARS相关文献为数据源,采用一种新兴的科学计量学分析方法——引文出版年光谱,对SARS领域进行整体分析,梳理SARS研究的历史起源（1890-2002年）和发展演化（2002-2020年）过程,得出SARS研究的峰值、演化规律、期刊分布等,为新型冠状病毒肺炎疫情的防治和研究提供情报支持。