US location of the adductor canal hiatus: morphologic study

In the lower extremities, the adductor canal hiatus is a site of predilection for arterial stenoses and occlusions. The high incidence of vascular disease in this region is thought to be due to a local factor. To gain more insight into the mechanisms leading to such disease, the authors used ultrasound to locate the adductor canal hiatus in dissecting room preparations and in healthy volunteers.     

Wirtschaftliche Vorteile aus Vertragsarztzulassung als nicht abnutzbares immaterielles Wirtschaftsgut

Abstrakt Der wirtschaftliche Vorteil aus einer Vertragsarztzulassung stellt ein nicht abnutzbares immaterielles Wirtschaftsgut dar.     

脱细胞羊皮基质的制备与性能检测

目的:制备一种廉价、安全而且来源丰富的生物敷料,以用于烧伤患者微粒皮移植后和削痂后创面的保护。方法:实验于2003-10/2007-03在积水潭医院烧伤研究所完成。①主要材料:健康山羊5只,纯种新西兰大白兔10只;戊二醛猪皮(清华源兴生物制品公司);冷冻保存的人皮(志愿者捐献)。②实验方法:山羊麻醉处死,去毛后取全层皮肤,通过反复冻融、配合超声震荡和洗脱液处理,在保证胶原支架完整情况下去除导致皮肤排斥反应的细胞成分,获得脱细胞羊皮基质,冷冻保存。③实验评估:利用常规病理检查和电子显微镜检查其有无明显细胞碎片残留;细菌真菌培养,测试其机械强度、亲水性和细胞毒性,通过动物埋藏实验确定其组织相容性,并与戊二醛交联的脱细胞猪皮以及冷冻保存的人皮作对照。结果:制备的脱细胞羊皮基质,常规病理检查、免疫组织化学染色、电子显微镜检查均未发现表皮和真皮细胞残留;细菌真菌培养呈阴性;为亲液固体,质感柔软有弹性,含水量、极限抗拉强度、应力-应变量、应力松弛特征、蠕变性等物理性能均与冷冻人皮相似,明显优于戊二醛猪皮;细胞毒性0级,在国家标准允许范围内;植入兔背部脊柱两侧的肌肉组织内后,能够与组织很好的融合,并诱导细胞和血管长入,组织相容性良好。结论:采用冻融法制备的脱细胞羊皮敷料安全、廉价、来源丰富,达到临床手术应用的保护性生物敷料标准。     

Phase I trial of "bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell" vaccine (FANG) in advanced cancer

We performed a phase I trial of FANG vaccine, an autologous tumor-based product incorporating a plasmid encoding granulocyte-macrophage colony-stimulating factor (GMCSF) and a novel bifunctional short hairpin RNAi (bi-shRNAi) targeting furin convertase, thereby downregulating endogenous immunosuppressive transforming growth factors (TGF) β1 and β2. Patients with advanced cancer received up to 12 monthly intradermal injections of FANG vaccine (1 × 10(7) or 2.5 × 10(7) cells/ml injection). GMCSF, TGFβ1, TGFβ2, and furin proteins were quantified by enzyme-linked immunosorbent assay (ELISA). Safety and response were monitored. Vaccine manufacturing was successful in 42 of 46 patients of whom 27 received ≥1 vaccine. There were no treatment-related serious adverse events. Most common grade 1, 2 adverse events included local induration (n = 14) and local erythema (n = 11) at injection site. Post-transfection mean product expression GMCSF increased from 7.3 to 1,108 pg/10(6) cells/ml. Mean TGFβ1 and β2 effective target knockdown was 93.5 and 92.5% from baseline, respectively. Positive enzyme-linked immunospot (ELISPOT) response at month 4 was demonstrated in 9 of 18 patients serially assessed and correlated with survival duration from time of treatment (P = 0.025). Neither dose-adverse event nor dose-response relationship was noted. In conclusion, FANG vaccine was safe and elicited an immune response correlating with prolonged survival. Phase II assessment is justified.     

On and off-target effects of telomere uncapping G-quadruplex selective ligands based on pentacyclic acridinium salts

Quadruplexes DNA are present in telomeric DNA as well as in several cancer-related gene promoters and hence affect gene expression and subsequent biological processes. The conformations of G4 provide selective recognition sites for small molecules and thus these structures have become important drug-design targets for cancer treatment.The DNA G-quadruplex binding pentacyclic acridinium salt RHPS4 (1) has many pharmacological attributes of an ideal telomere-targeting agent but has undesirable off-target liabilities. Notably a cardiovascular effect was evident in a guinea pig model, manifested by a marked and sustained increase in QTcB interval. In accordance with this, significant interaction with the human recombinant β2 adrenergic receptor, and M1, M2 and M3 muscarinic receptors was observed, together with a high inhibition of the hERG tail current tested in a patch clamp assay.Two related pentacyclic structures, the acetylamines (2) and (3), both show a modest interaction with β2 adrenergic receptor, and do not significatively inhibit the hERG tail current while demonstrating potent telomere on-target properties comparing closely with 1. Of the two isomers, the 2-acetyl-aminopentacycle (2) more closely mimics the overall biological profile of 1 and this information will be used to guide further synthetic efforts to identify novel variants of this chemotype, to maximize on-target and minimize off-target activities.Consequently, the improvement of toxicological profile of these compounds could therefore lead to the obtainment of suitable molecules for clinical development offering new pharmacological strategies in cancer treatment.