全球单克隆抗体药物研发现状及发展趋势

单克隆抗体药物以其独特的作用机制及高效性,在恶性肿瘤和自身免疫疾病的治疗中发挥了不可估量的重要作用,成为全球的研发热点。基于科睿唯安旗下的Cortellis数据库,采用定量分析和专家智慧相结合的方法,从总体研发和商业化现状、主要国家/地区、技术和种类、靶点及作用机制、市场份额、产品交易多个维度展现出全球单克隆抗体药物的研发和商业化全景。分析结果显示:全球已上市的单克隆抗体药物有133个,其中已上市的人源化单克隆抗体药物占已上市的单克隆抗体药物总数的37. 6%。作用靶点主要集中在HER、TNF、CD20、PD-1/L1、VEGF以及CD3,其中作为HER2酪氨酸激酶受体抑制剂的药物数量最多。美国在单克隆抗体药物研发和商业化方面遥遥领先,中国在研和上市的单抗隆抗体药物总数排名第二,但中国上市的单抗隆抗体药物数量仅8个。2017年销售额高于10亿美元的单克隆抗体药物有22个。全球单克隆抗体药物的交易数量共有1 408次,药物开发与商业化许可是最主要的交易方式。未来,单克隆抗体药物的发展趋势将朝着新靶点、新适应症和新用药方案的方向发展,将会产生更多"重磅炸弹药物"。     

人源抗体制备及临床应用研究进展

与常规治疗药物相比,抗体药物具有靶向性强、特异性好等优点,其作为一类重要的治疗性药物,近年来在临床中的应用逐渐增多,为疾病的治疗提供了新的选择,应用范围逐渐从肿瘤、自身免疫性疾病及慢性炎症扩展到心血管和感染性等疾病中。人源抗体的全部结构是由人类抗体基因所编码的,因此避免了异种蛋白长期应用引起的不良反应,加之人源抗体制备技术的不断发展完善,使其逐渐成为治疗性抗体研发的首要选择。综述了近年来治疗性人源抗体的主要制备技术及其在临床中应用的最新进展,同时探讨了人源抗体制备技术的不足之处,以期为人源抗体的发展提供借鉴和思路。     

Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases

The chemokine receptor CXCR2 and its ligands are implicated in the progression of tumours and various inflammatory diseases. Activation of the CXCLs/CXCR2 axis activates multiple signalling pathways, including the PI3K, p38/ERK, and JAK pathways, and regulates cell survival and migration. The CXCLs/CXCR2 axis plays a vital role in the tumour microenvironment and in recruiting neutrophils to inflammatory sites. Extensive infiltration of neutrophils during chronic inflammation is one of the most important pathogenic factors in various inflammatory diseases. Chronic inflammation is considered to be closely correlated with initiation of cancer. In addition, immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) against T cells attenuate the anti-tumour effects of T cells and promote tumour invasion and metastasis. Over the last several decades, many therapeutic strategies targeting CXCR2 have shown promising results and entered clinical trials. In this review, we focus on the features and functions of the CXCLs/CXCR2 axis and highlight its role in cancer and inflammatory diseases. We also discuss its potential use in targeted therapies.     

Sensor-to-body calibration procedure for clinical motion analysis of lower limb using magnetic and inertial measurement units

Magnetic and Inertial measurement units (MIMUs) have become exceedingly popular for ambulatory human motion analysis during the past two decades. However, measuring anatomically meaningful segment and joint kinematics requires virtual alignment of the MIMU frame with the anatomical frame of its corresponding segment. Therefore, this paper presents a simple calibration procedure, based on MIMU readouts, to align the inertial frame of the MIMU with the anatomical frames, as recommended by ISB. The proposed calibration includes five seconds of quiet standing in a neutral posture followed by ten consecutive hip flexions/extensions. This procedure will independently calibrate MIMUs attached to the pelvis, thigh, shank, and foot. The accuracy and repeatability of the calibration procedure and the 3D joint angle estimation were validated against the gold standard motion capture system by an experimental study with ten able-bodied participants. The procedure showed high test-retest repeatability in aligning the MIMU frame with its corresponding anatomical frame, i.e., the helical angle between the MIMU and anatomical frames did not significantly differ between the test and retest sessions (except for thigh MIMU). Compared to previously introduced procedures, this procedure attained the highest inter-participant repeatability (inter-participant coefficient of variations of the helical angle: 20.5–42.2%). Further, the proposed calibration would reduce the offset errors of the 3D joint angle estimation (up to 12.8 degrees on average) compared to joint angle estimation without calibration (up to 26.3 degrees on average). The proposed calibration enables MIMU to measure clinically meaningful gait kinematics.     

株具有荚膜的白假丝酵母菌的分离与鉴定*

取临床标本(性病门诊病人阴道分泌物)直接涂片染色镜检及用沙保氏琼脂平板分离培养、作涂片革兰染色镜检、出芽试验、厚膜孢子形成试验、糖发酵试验等鉴定菌种;小白鼠与家兔试验、荚膜肿胀试验、透射电镜等观察荚膜,观察白假丝酵母菌临床分离菌株(C1-1、C1-2、C1-3、C1-4)的荚膜结构并探讨其形成条件。结果显示:(1)C1-1、C1-2、C1-3、C1-4四株临床分离菌株均为革兰阳性、念珠状菌;能形成芽管、假菌丝、厚膜孢子;能发酵葡萄糖和麦芽糖产酸又产气;发酵蔗糖产酸不产气;不发酵乳糖。(2)在感染小白鼠及家兔体内均可形成荚膜,荚膜层的厚度可因不同环境而有显著差异(P<0·01或<0·05),边界明显;荚膜肿胀试验阳性。4株临床分离菌株均可被鉴定为具有荚膜的白假丝酵母菌。     

胸部双源性疾病外科治疗的临床决策

胸部双源性疾病随人口的老龄化而逐年增加,而老年人的心肺及各种脏器功能随年龄的增长逐渐衰退,并发症多,手术风险大,对此类病人的外科治疗如何做出正确的临床医疗决策呢？我们以循证医学理论为基础,努力做到临床医疗决策的科学性,治疗方案的合理性,大胆尝试,逐步从分期手术向一期手术过渡,既达到了解决病人疾苦,救治病人的目的,又解决了医疗需求的增加和卫生资源短缺的矛盾,取得了满意的效果,降低了医疗成本,节约了医疗资源,产生了明显的社会和经济效益。     

自拟柴芍护膜汤联合莫沙必利治疗反流性食管炎的临床效果观察

目的:研究自拟柴芍护膜汤联合莫沙必利治疗反流性食管炎的临床效果和可能机制。方法:选择2015年12月～2018年12月我院内科杂病门诊治疗的70例反流性食管炎患者,将其随机分为两组。对照组服用莫沙必利,每次5 mg,每天3次;观察组联合服用自拟柴芍护膜汤以及莫沙必利。比较两组患者治疗后的临床治疗效果,治疗前后泛酸、烧心、脘腹胀满、嗳气、呃逆、情志抑郁、善太息、食欲不振以及嘈杂等症状的严重程度、血浆胃动素和血清胃泌素水平的变化。结果:治疗后,观察组的有效率为91.43%,明显高于对照组(71.43%,P0.05)。两组治疗后的泛酸、烧心、脘腹胀满、嗳气、呃逆、情志抑郁、善太息、食欲不振以及嘈杂评分均较治疗前明显降低(P0.05),且观察组的上述症状评分明显低于对照组(P0.05);两组治疗后的血浆胃动素和血清胃泌素水平均较治疗前明显升高(P0.05),且观察组以上指标均明显高于对照组(P0.05)。结论:自拟柴芍护膜汤联合莫沙必利能有效改善反流性食管炎的临床症状,其作用机制可能与提高血浆胃动素和血清胃泌素水平有关。     

健脾安肠汤联合匹维溴胺治疗肠易激综合征的临床疗效及对血清5-HT、CGRP、SP、VIP水平的影响

目的:探讨健脾安肠汤联合匹维溴胺治疗肠易激综合征的临床疗效及对血清5-羟色胺(5-HT)、降钙素基因相关肽(CGRP)、结肠黏膜P物质(SP)、血管活性肠态(VIP)水平的影响。方法:选择2017年1月至2017年12月本院接诊的98例肠易激综合征患者作为研究对象,按随机数表法分为观察组(n=45)和对照组(n=53),对照组单纯采用匹维溴胺进行治疗,观察组在此基础上联合健脾安肠汤进行治疗。比较两组患者的临床疗效及治疗前后胃肠症状改善情况、血清5-HT、CGRP、SP、VIP水平、炎性因子水平、焦虑(SAS)、抑郁(SDS)评分的变化。结果:治疗后,观察组总有效率(93.33%)心脏高于对照组(71.70%,P0.05);观察组患者恶心呕吐、腹痛腹泻、排便次数及大便性质症状评分,血清5-HT、CGRP、SP、VIP、IL-8、IL-6水平、焦虑及抑郁评分均明显低于对照组(均P0.05),而血清IL-10水平显著高于对照组(P0.05)。结论:健脾安肠汤联合匹维溴胺治疗肠易激综合征的临床效果显著优于单纯采用匹维溴胺治疗,可有效调节机体胃肠激素分泌和临床症状,提高患者患者生活质量。     

呼吸窘迫综合征早产儿血清VA、PCT、TNF-α及CRP水平的表达及临床意义

目的:探讨呼吸窘迫综合征(RDS)早产儿血清维生素A(VA)、降钙素原(PCT)、肿瘤坏死因子-α(TNF-α)及C反应蛋白(CRP)水平的表达及临床意义。方法:选取2015年2月～2018年5月期间青岛市妇女儿童医院收治的90例RDS早产儿纳入观察组,根据RDS分级将观察组分为轻度组48例,中重度组42例。另选取同期于本院出生的非RDS早产儿35例作为对照组。根据血清VA水平将125例早产儿分为VA缺乏组(n=72),亚临床VA缺乏组(n=36),正常组(n=17)。比较观察组与对照组、轻度组与中重度组早产儿血清VA、PCT、TNF-α及CRP水平,比较不同血清VA水平早产儿的RDS发病情况,分析观察组早产儿血清VA与PCT、TNF-α及CRP水平的相关性。结果:观察组早产儿血清VA水平明显低于对照组(P0.05),而观察组早产儿血清PCT、TNF-α、CRP明显高于对照组(P0.05)。中重度组早产儿血清VA水平与轻度组比较差异无统计学意义(P0.05),而中重度组早产儿血清PCT、TNF-α、CRP水平明显高于轻度组(P0.05)。随着血清VA水平的升高,RDS发病率逐渐降低,组间比较差异有统计学意义(P0.05)。Pearson相关性分析显示,观察组早产儿血清VA与PCT、TNF-α及CRP水平无显著相关性(P0.05)。结论:RDS早产儿血清VA与PCT、TNF-α及CRP水平均存在明显异常,但四者无明显相关性,血清VA相对较低者更易发生RDS,临床可通过及时干预VA水平以降低RDS的发生风险。