Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women

Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.     

Enucleation combined with orbital implants for malignant melanoma of the uvea

Advanced malignant melanomas of the uvea unsuited for an eye salvaging approach require enucleation of the tumor containing eye. A series of 68 patients is reported who underwent enucleation combined with insertion of a spherical dura-encased implant after 30 Gray pre-irridiation therapy of the orbit. Postoperative results with special attention to cosmetic outcome and motility of the prosthesis suggest that the insertion of an orbital implant should be preferred to the enucleation with no implant.     

Vectorization of morpholino oligomers by the (R-Ahx-R)4 peptide allows efficient splicing correction in the absence of endosomolytic agents.

The efficient and non-toxic nuclear delivery of steric-block oligonucleotides (ON) is a prerequisite for therapeutic strategies involving splice correction or exon skipping. Cationic cell penetrating peptides (CPPs) have given rise to much interest for the intracellular delivery of biomolecules, but their efficiency in promoting cytoplasmic or nuclear delivery of oligonucleotides has been hampered by endocytic sequestration and subsequent degradation of most internalized material in endocytic compartments. In the present study, we compared the splice correction activity of three different CPPs conjugated to PMO(705), a steric-block ON targeted against the mutated splicing site of human beta-globin pre-mRNA in the HeLa pLuc705 splice correction model. In contrast to Tat48-60 (Tat) and oligoarginine (R(9)F(2)) PMO(705) conjugates, the 6-aminohexanoic-spaced oligoarginine (R-Ahx-R)(4)-PMO(705) conjugate was able to promote an efficient splice correction in the absence of endosomolytic agents. Our mechanistic investigations about its uptake mechanisms lead to the conclusion that these three vectors are internalized using the same endocytic route involving proteoglycans, but that the (R-Ahx-R)(4)-PMO(705) conjugate has the unique ability to escape from lysosomial fate and to access to the nuclear compartment. This vector, which has displays an extremely low cytotoxicity, the ability to function without chloroquine adjunction and in the presence of serum proteins. It thus offers a promising lead for the development of vectors able to enhance the delivery of therapeutic steric-block ON in clinically relevant models.     

北京自然人群载脂蛋白E基因多态性频率分布研究

应用聚合酶链反应 限制性片段长度多态性技术 (PCR RFLP) ,以北京自然人群为基础 ,采用分层随机抽样的方法进行横断面研究 ,对 1 0 46人进行apoE基因分型 ,并分析不同特点人群apoE基因频率分布特点。结果表明 :1 )本组人群ε2、ε3、ε4基因频率分别为 9.1 %、81 .2 %和 9.7% ,男女和各年龄组间基因频率无显著差异 ;2 )与欧美国家相比 ,本组人群ε2基因频率增高 ,ε4频率减低 ,与日本人群相比也有相同趋势 ;3 )在空腹血糖受损及糖尿病人群中ε2频率明显增高 ;4)在高胆固醇血症人群中ε2频率减低、ε4基因频率增高     

The treatment of associated intracranial aneurysms and arteriovenous malformations.

Cerebral arterial aneurysm associated with arteriovenous malformation (AVM) has been described with a variable incidence, averaging 10% of AVM cases. The present series includes 39 patients with this association, derived from a total of 400 patients with AVM's evaluated and treated since 1970. The aneurysms are classified into four major groups, each carrying particular therapeutic implications. Optimum treatment of these lesions is based in part on a knowledge of the hemodynamic alterations associated with the AVM's. In most of these cases, the symptomatic lesion was treated first; occasionally, when feasible, both lesions were treated during the same operation. All patients had some form of treatment, either surgical or endovascular, directed to at least one of the two types of lesions. All symptomatic lesions were treated and all ruptured aneurysms were obliterated. There were no deaths in this series.     

红藻氨酸作用后海马神经元胞膜表面的超微结构的原子力显微镜观察

目的 观察原代培养神经元在红藻氨酸(KA)作用下细胞表面形态的三维构像变化。方法 利用原子力显微镜(AFM)对大鼠海马神经元经不同浓度的KA(25和250μmol／L，50和100nmol／L)分别作用10min和100min后的表面结构进行纳米级水平扫描和观测。结果 正常海马神经元表面光滑，起伏均匀、规律；KA作用后神经元呈退行性改变，表现为胞体肿胀，胞膜表面粗糙，出现隆起和“孔洞”样结构，并且其变化程度分别与作用时问和KA浓度呈量-效关系。结论 KA对海马神经元毒性作用后胞膜表面超微结构所产生的明显变化，可借助AFM清晰观察，并定量分析。