A Phase 1B Study of Dulanermin in Combination With Modified FOLFOX6 Plus Bevacizumab in Patients With Metastatic Colorectal Cancer

ObjectivesThe study objectives were to evaluate the safety, tolerability, and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced, recurrent, or metastatic colorectal cancer.Patients and MethodsA total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed.ResultsIn the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7).ConclusionsOverall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population.     

TRAIL联合顺铂诱导骨肉瘤HOS-8603细胞凋亡研究

目的研究TRAIL联合顺铂诱导HOS-8603细胞的凋亡及其机制。方法 MTT法分别测定TRAIL,顺铂,和TRAIL+顺铂对HOS-8603细胞的抑制率,流式细胞法测定亚G1期细胞百分率及PI和Rh123双染色后细胞的ΔΨm。结果三组分别由TRAIL、顺铂、TRAIL+顺铂处理过的HOS-8603细胞用MTT法测抑制率分别为29%、33.6%、58.5%。随着药物作用时间增加,HOS-8603细胞凋亡数增加和ΔΨm降低(P<0.01),两者呈直线相关。结论 TRAIL和顺铂能协同诱导HOS-8603细胞凋亡,其机制可能是通过使线粒体膜通透性转运孔开放,ΔΨm降低来实现的。     

Oncolytic adenovirus encoding tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits the growth and metastasis of triple-negative breast cancer

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising cancer therapeutic target due to its selective apoptosis-inducing effect in cancer cells. To efficiently deliver TRAIL to the tumor cells, an oncolytic adenovirus (p55-hTERT-HRE-TRAIL) carrying the TRAIL coding sequence was constructed. In the present study, we aimed to investigate the effect of p55-hTERT-HRE-TRAIL on the growth and metastasis of triple-negative breast cancer (TNBC). We observed that infection of the recombinant adenovirus resulted in expression of TRAIL and massive cell death in a TNBC cell line MDA-MB-231. This effect is much weaker in MCF-10A, which is a normal breast cell line. Administration of P55-HTERT-HRE-TRAIL significantly reduced orthotopic breast tumor growth and extended survival in a metastatic model. Our results suggest the oncolytic adenovirus armed with P55-HTERT-HRE-TRAIL, which exhibited enhanced anti-tumor activity and improved survival, is a promising candidate for virotherapy of TNBC.     

Conatumumab: a novel monoclonal antibody against death receptor 5 for the treatment of advanced malignancies in adults

Introduction: Advanced malignancies that are refractory to standard chemotherapy have few treatment options. Conatumumab is an investigational, fully human monoclonal agonist antibody directed at human death receptor DR5, which is expressed in multiple advanced cancers.

Areas covered: The rationale for the use of conatumumab based on in vitro, in vivo, Phase I, and Phase II data will be discussed.

Expert opinion: Conatumumab, at a dose of 20 mg/kg every 2 weeks, has demonstrated acceptable safety and tolerability in patients with advanced tumors based on available and published data. Further clinical trials are underway evaluating the use of conatumumab in combination with chemotherapeutic and targeted agents.     

TRAIL及TRAIL受体在慢性乙型肝炎患者外周血淋巴细胞的表达

目的　探讨TRAIL(TNF relatedapoptosis inducingligand)及TRAIL受体 (TRAIL R)mRNA在慢性乙型肝炎患者外周血淋巴细胞 (peripheralbloodlymphocytes,PBL)中的表达。方法　分离 2 0例正常人、2 4例慢性乙型肝炎患者及 2 4例慢性重型乙型肝炎患者之PBL ,体外单独或与植物血凝素(PHA)共同培养 4 8h ,荧光素吖啶橙和溴乙啶染色PBL ,观察其凋亡细胞比例 ,采用逆转录 聚合酶链反应 (RT PCR)方法检测TRAIL、TRAIL RmRNA在PBL中的表达。结果　与正常对照组相比 ,活化诱导的淋巴细胞凋亡在慢性乙型肝炎患者明显增高 ,而在慢性重型肝炎患者则降低 ,差异有显著性 (P<0 .0 1)。PHA活化前 ,TRAILmRNA在上述 3组研究对象外周血淋巴细胞均不表达 ;PHA活化后 ,其表达明显上调 ,且慢性乙型肝炎组高于正常对照组 ,慢性重症肝炎组低于正常对照组 ,差异有显著性(P <0 .0 1)。 4个TRAIL R的mRNA在 3组研究对象外周血淋巴细胞均有表达 ,两两比较差异无显著性 (P >0 .0 5 )。经PHA活化后 ,TRAIL R2mRNA表达明显上调 (P <0 .0 1) ,TRAIL R3mRNA表达完全消失 ,TRAIL R1与 R4的mRNA表达无明显改变 (P >0 .0 5 )。结论　慢性乙型肝炎患者外周血淋巴细胞存在凋亡紊乱现象 ,TRAIL参与了乙型肝炎患者外周血淋巴细胞活化诱导细胞死亡 (     

Method for spatially interleaving two images to halve EPI readout times: two reduced acquisitions interleaved (TRAIL).

A new MRI method is presented that can generate images using half the normal readout time or, more usefully, half the number of phase-encode steps, combining two readouts per excitation. However, the corresponding data are interleaved in image space-not in k-space, as in many other fast techniques. This gives a resilience to the phase-related artifacts that can occur in many other techniques due to subject motion. A modified stimulated-echo experiment is used to create two low-resolution images from a single sequence. The magnetization that contributes to these images is nonuniformly distributed within each pixel, forming two sinusoidal waves in quadrature, with an oscillation period of exactly two pixels. Since only half of each pixel contributes significant signal, the two images can be interleaved to create a full image with twice as many pixels and double the resolution. When the technique is used in the phase-encode direction, the effective imaging time is halved, though with two readouts per TR period. When two half-length echo-planar readouts are used, the method can also reduce blurring and distortion by halving the effective readout time for echo-planar imaging (EPI). For even further improvements, the technique can be combined with partial Fourier or parallel imaging.     

FASL、TRAIL在慢性乙型肝炎患者外周血淋巴AICD中的作用

目的:探讨FASL、TRAIL在慢性乙型肝炎患者外周血淋巴细胞(Peripheral blood lymphocytes,PBLs)活化诱导细胞凋亡(activation induced cell death,AICD)中的作用。方法:分离20例正常人、24例慢性乙型肝炎患者及24例慢性重型乙型肝炎患者的PBLs,体外单独或与植物血凝素(PHA)共同培养48小时,以逆转录-聚合酶链反应(RT-PCR)与免疫组化SABC法检测FASL、TRAIL.在慢性乙肝患者PBLs的表达。结果:PHA活化前,FASL.mRNA、TRAIL mRNA在上述3组研究对象外周血淋巴细胞均不表达;PHA活化后;二者表达明显上调,且慢性乙型肝炎组高于正常对照组,慢性重症肝炎组低于正常对照组,差异有显著性(P<0.01)。正常人静息的外周血淋巴细胞不表达FASL和弱表达TRAIL,经PHA活化后,二者表达均明显上调(P<0.01)。结论:FASL、TRAIL参与了乙型肝炎患者外周血淋巴细胞AICD过程,并可能是其重要效应分子。     

抗人DR5单克隆抗体mDRA-6对HL-60细胞的诱导凋亡作用

目的 观察抗死亡受体5(DR5)单克隆抗体nDRA-6对HL-60细胞的凋亡作用.方法 制备抗人DR5单克隆抗体mDRA-6;荧光显微镜下观察mDRA-6作用后HL-60细胞的形态变化;MTT法测定不同浓度mDRA-6在不同作用时间对HL-60细胞存活的影响;通过FITC-Annexin V及PI标记细胞,以流式细胞仪检测mDRA-6对HL-60细胞凋亡率的影响;琼脂糖凝胶电泳检测mDRA-6对HL-60细胞DNA片段化的影响.结果 mDRA-6导致HL-60细胞染色质浓缩、断裂,细胞出芽,凋亡小体形成;mDRA-6对HL-60细胞具有明显的杀伤作用,24ng/mL mDRA-6作用HL-60细胞10 h,细胞死亡率达21.2%;1μg/mL的mDRA-6作用8 h,可使HL-60细胞死亡44.1%;Annexin V及PI双染显示,10μg/mL mDRA-6作用2 h,HL-60细胞的凋亡率达48.1%;20μg/mLmDRA-6作用HL-60细胞3 h,DNA琼脂糖凝胶电泳显示明显的"梯形"条带.结论 抗DR5单克隆抗体mDRA-6具有诱导HL-60细胞凋亡作用.     

007 妊娠免疫耐受与器官移植

正常妊娠显示母体对同种异体胎儿的免疫耐受.最近研究表明母胎耐受与非经典HLA-Ⅰ类分子HLA-G及HLA-E表达和TNF相关的凋亡诱导配体(TNF-related apoptosis-inducing ligand,TRAIL))及其受体TRAILR相互作用以及和Fas配体(FasL)表达有关.本文就这些分子在母胎耐受中的作用机制及在移植免疫中的应用前景作一综述.