噬菌体展示肽库技术在胃癌研究与治疗中的进展

胃癌(Gastric cancer)是我国最常见的消化道肿瘤之一。近几年,胃癌早期诊断以及低副作用的有效治疗已经成为研究人员重点关注的方向和领域。噬菌体展示肽库技术 (phage display library, PDL)作为分析蛋白质之间相互作用的有效方法,具有简便、高效、高通量等优点,这使得PDL在胃癌的诊断检测和靶向治疗领域展示出了极大的研究价值和潜力。本文就目前PDL技术在胃癌诊断和治疗领域中的研究进展进行综述。     

Erdheim–Chester disease

Erdheim–Chester disease (ECD) is a rare but increasingly recognized multi-system disorder. Its diagnosis and treatment require integration of clinical information, imaging studies, and pathology studies. Of note, ECD can now be defined as a clonal myeloid disorder due to mutations which activate mitogen-activated protein kinase (MAPK) pathways and where an inflammatory milieu is important in the pathogenesis and clinical manifestations of the disease. Biopsy demonstrating characteristic histopathologic features in addition to clinical and radiographic features, most often sclerosing long bone involvement, is required to establish a diagnosis. Detection of somatic MAPK pathway mutations can also assist in the differential diagnosis of ECD and related histiocytic neoplasms. Also, genetic analysis establishing BRAF and RAS mutational status is critical in all ECD patients, as these features will impact therapy with MAPK inhibition. Therapy is recommended at diagnosis in all patients, except for those patients with minimally symptomatic disease. Prospective therapeutic trials are essential to furthering therapeutic progress in ECD.     

平阳霉素量子点聚乳酸羟基乙酸纳米粒的制备

目的为研究靶向治疗口腔癌颈淋巴结转移灶,制备一种集靶向化疗、定位、实时监测为一体的纳米粒(Nanoparticles,NPs)。方法以平阳霉素(pingyangmycin,PYM)为模型药物,以量子点(quantum dots,QDs)为荧光探针,以聚乳酸羟基乙酸(polylactic-co-glycolic acid,PLGA)为载体,以粒径、荧光性能、载药量和包封率为质量控制指标,通过正交实验设计,用复乳法制备平阳霉素量子点聚乳酸羟基乙酸纳米粒(PYM-QD-PLGA-NPs)。结果经优化制备的PYM-QD-PLGA-NPs包封率为(78.1±2.1)%,载药率为(5.9±0.3)%,平均粒径245.4 nm,电位(-6.68±4.11)mV,具备与QDs相似的荧光性能。结论 PYM-QD-PLGA-NPs具备一定的PYM包载率和QDs荧光性能,符合淋巴靶向的粒径要求,理论上通过口腔癌周注射,可靶向、定位、监测并治疗颈淋巴结转移灶。     

疟原虫环子孢子蛋白的研究进展

环子孢子蛋白(circumsporzoite protein,CSP)是疟原虫成熟子孢子表面的锚定蛋白,约含400个氨基酸,由N端保守I区、种属特异性的中央重复区和C端保守Ⅱ区构成。CSP在疟原虫的迁移、靶细胞入侵和增殖过程中发挥重要作用。近年研究显示,CSP在疟疾疫苗和靶向给药系统中具有良好的应用前景。本文对疟原虫CSP的结构特征、功能及其应用前景作一综述。     

胃肠道间质瘤的分子学机制及靶向治疗

C-kit/PDGFRA基因发生功能获得性突变和因此引发的KIT蛋白自主磷酸化是胃肠道间质瘤(gastrointestinal stromal tumors,GISTs)发生过程中最具特征性的分子机制.这一发现使得imatinib靶向治疗GISTs成为可能并取得重大疗效,但研究发现不同类型的GISTs对imatinib治疗的反应也不尽相同,并且随着其临床应用的增加,耐药性及不良反应也随之出现,迫使imatinib临床停药或改为二线用药.因此,GISTs是由不同生物学机制引发的一组疾病,本文就GISTs的分子生物学机制及靶向治疗药物作一综述.     

Notch信号通路在肿瘤中的研究进展

【摘要】 Notch信号通路是一条影响细胞命运、保守而重要的信号转导通路,几乎涉及所有细胞的生长活动,在调节细胞分化、增殖和凋亡,及在一系列生理、病理过程中都起着关键性的作用,并在肿瘤的发生、发展中也发挥了至关重要的作用。近年对Notch信号通路的研究不断加深和完善,使其与肿瘤的密切关系得到了充分呈现,并有望针对相关靶点设计靶向药物,为肿瘤治疗提供新方向。     

A Randomized,Double-Blind,Dose-Finding,Multicenter, Phase 2 Study of Radium Chloride (Ra 223) in Patients with Bone Metastases and Castration-Resistant Prostate Cancer

Background

Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile.

Objective

To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases.

Design, setting, and participants

In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n = 41), 50 kBq/kg (n = 39), or 80 kBq/kg (n = 42). The study compared the proportion of patients in each dose group who had a confirmed decrease of ≥50% in baseline prostate-specific antigen (PSA) levels.

Outcome measurements and statistical analysis

Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups.

Results and limitations

The study met its primary end point with a statistically significant dose–response relationship in confirmed ≥50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p = 0.0297). A ≥50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p < 0.0001). The most common treatment-related AEs (≥10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. Potential limitations include small patient numbers and differences among dose groups at baseline.

Conclusions

Ra 223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra 223 may affect cancer-related outcomes. Ra 223 was well tolerated at all doses.

Trial registration

ClinicalTrials.gov: NCT00337155.     

对胃癌预后判断的分子标志物以及治疗靶点的研究

相同临床分期的胃癌患者仍然存在明显不同的预后状态,这使得根据临床分期的治疗规约存在实际上的不足.采用系统生物学方法为主的手段寻找与患者预后生存相互关联的分子标志物,对胃癌进行更细节的分子分型,从而为个体化的诊疗提供依据.一些标志物可以用于胃癌的靶向性治疗,HER2抗体是目前指南中唯一通过的靶向类药物.随着靶向类药物的不断研发与演进,不久的将来,我们可以看到更多的靶向类药物进入胃癌临床.     

非病毒靶向载体递送小干扰RNA的研究进展

近年来由小干扰RNA(siRNA)所介导的RNA干扰(RNAi)技术发展迅速,如何高效、安全地将siRNA转运至靶组织是决定这一技术应用前景的关键问题。本文重点围绕构建siRNA的非病毒靶向载体递送系统的研究进展进行综述。     

低强度聚焦超声靶向爆破微泡

目的 探讨自制低强度聚焦超声（LIFU）体外靶向爆破微泡范围、空间分布,及在兔肝脏组织中应用LIFU辐照载紫杉醇脂质微泡（PLM）的定位控释情况。方法 ①采用4种不同声强（0.3、0.6、0.9、1.2 W/cm2）LIFU（频率1 MHz,焦距160 mm,占空比50%）分别辐照含脂质微泡的水囊,同时从不同切面观察并记录水囊内微泡爆破范围及空间分布形态;②选取新西兰大白兔10只,随机平均分为聚焦超声组（A组）和非聚焦超声组（B组）;对实验兔静脉注射PLM后,对A、B组分别采用LIFU和非聚焦超声定位辐照肝脏2 min;辐照后1 h处死实验兔,取焦域中心及距离中心1 cm、2 cm、3 cm处的肝脏组织,采用反相高效液相色谱法测定各肝脏组织内的紫杉醇含量。结果 ①LIFU体外定位爆破微泡范围局限、形状规则,爆破范围随声强增高而增大;②A组辐照中心处紫杉醇浓度最大,距离中心处越远,紫杉醇浓度越低（F=201.81,P〈0.05）;B组中各位置紫杉醇浓度的差异无统计学意义（F=1.36,P〉0.05）;辐照中心处,A组紫杉醇浓度高于B组（t=5.28,P〈0.05）。结论 LIFU能够实现体内外靶向爆破微泡,其聚焦部位和微泡爆破范围可调。