人端粒酶逆转录酶启动子介导的靶向性肿瘤基因治疗的研究进展

端粒酶与肿瘤发生发展的关系是近年来肿瘤研究领域的热点之一．端粒的磨耗限制大多数体细胞的复制,肿瘤细胞主要通过转录上调端粒酶限制成分催化亚基端粒酶逆转录酶（hTERT）维持端粒长度．由于hTERT启动子区域已被克隆,其特点也已被鉴定,hTERT启动子介导的靶向性肿瘤基因治疗成为研究的热点．我们综述了hTERT启动子介导的靶向性肿瘤基因治疗最新研究进展．     

Cross-resistance to cisplatin in cells with acquired resistance to copper

Purpose Cells selected for resistance to cisplatin (DDP) demonstrate cross-resistance to copper (Cu) suggesting one or more common mechanisms of cellular defense. We sought to determine whether cells selected for resistance to Cu are cross-resistant to DDP.Materials and methods Parental HuH7 human hepatoma cells and the CuR27 Cu-resistant subline were compared for sensitivity to Cu and DDP by clonogenic assay, and with respect to drug uptake and efflux by measuring cellular Cu and Pt content.Results CuR27 cells were found to be 1.8-fold resistant to Cu and 8.6-fold cross-resistant to DDP. Changes in the cellular pharmacokinetics of Cu in the CuR27 cells were paralleled by changes in the kinetics of DDP. The accumulations of Cu and DDP measured at 1 min were, respectively, 36% and 26% of those in the parental HuH7 cells. The initial rate of efflux from the CuR27 cells was 6.2-fold faster for Cu and 2.5-fold faster for DDP than from the HuH7 cells. Cu reduced the accumulation of DDP in the HuH7 cells in a concentration-dependent manner and vice versa. DDP also reduced the efflux of Cu. Western blot analysis demonstrated that expression of the Cu exporter ATP7B was increased 3.9-fold in the CuR27 cells.Conclusions In this model system, cross-resistance between Cu and DDP was bidirectional and accompanied by parallel changes in the cellular pharmacokinetics of both compounds. The results are consistent with the idea that transporters and chaperones that normally mediate Cu homeostasis also directly or indirectly modulate the accumulation of DDP.Abbreviations DDP Cisplatin - PBS Phosphate-buffered saline - TBS Tris-buffered saline     

Medical management of advanced heart failure

Context  Advanced heart failure, defined as persistence of limiting symptoms despite therapy with agents of proven efficacy, accounts for the majority of morbidity and mortality in heart failure. Objective  To review current medical therapy for advanced heart failure. Data Sources  We searched MEDLINE for all articles containing the term advanced heart failure that were published between 1980 and 2001; EMBASE was searched from 1987-1999, Best Evidence from 1991-1998, and Evidence-Based Medicine from 1995-1999. The Cochrane Library also was searched for critical reviews and meta-analyses of congestive heart failure. Study Selection  Randomized controlled trials of therapy for 150 patients or more were included if advanced heart failure was represented. Other common clinical situations were addressed from smaller trials as available, trials of milder heart failure, consensus guidelines, and both published and personal clinical experience. Data Extraction  Data quality was determined by publication in peer-reviewed literature or inclusion in professional society guidelines. Data Synthesis  A primary focus for care of advanced heart failure is ongoing identification and treatment of the elevated filling pressures that cause disabling symptoms. While angiotensin-converting enzyme inhibitors and -adrenergic agents can slow disease progression and prolong survival, titration and tolerability often present challenges. Most patients are not eligible for surgical intervention but do benefit from a medical regimen tailored to individual clinical and hemodynamic profiles and from heart failure management programs that reduce rehospitalization. Survival ranges from 80% at 2 years for patients rendered free of congestion to less than 50% at 6 months for patients with refractory symptoms, in whom end-of-life options may include hospice care and inactivation of implantable defibrillators. Conclusions  Current management of advanced heart failure is based more on consensus than on randomized trials. Systematic investigation should address not only new therapies but also strategies for selecting and optimizing therapies already available.      

Central nervous system high-resolution magnetic resonance imaging: effect of increasing spatial resolution on resolving power

Resolving power is a useful measure of the magnetic resonance (MR) imager-determined ability to discriminate subtle disease. Optimizing the resolving power produces the best MR images. The resolving power improves with higher spatial resolution, signal-to-noise ratio, and object contrast. Resolving power degrades with increased patient motion, which can be associated with prolonged imaging times. High and low object contrast 0.35-T MR images of the central nervous system are compared at different levels of spatial resolution and signal-to-noise ratios. In systems that have a marginal signal-to-noise ratio, the resolving power can actually decrease when higher spatial resolution is used due to further lowering of signal-to-noise ratio and to increased motion resulting from longer imaging times. This decreases the conspicuity of small, low contrast lesions.     

Low-artifact intravascular devices: MR imaging evaluation

Flow-phantom magnetic resonance (MR) imaging, with use of both spin-echo (SE) and gradient-echo (GRE) techniques at 1.5 T, was performed on the percutaneous Greenfield (beta-III titanium alloy [TMA wire]), Amplatz (MP32-N alloy), and Simon nitinol filters and TMA wire facsimiles of the bird's nest, Gunther, new retrievable, and Amplatz vena caval filters. SE imaging allowed detection of thrombi as small as 5 X 5 mm trapped within the percutaneous Greenfield, Simon nitinol, and TMA-wire facsimile filters; with the MP32-N Amplatz filter, a larger volume of thrombus (10 X 20-mm clots) was necessary for clot detection. GRE imaging allowed detection of intraluminal tilting of the percutaneous Greenfield and facsimile Amplatz (TMA-wire) filters. GRE imaging was useful for demonstrating postfilter turbulence due to clots, which was greatest for the Amplatz filter. Imaging of facsimile vascular devices made of tantalum or TMA wire did not cause the severe "black-hole" MR artifacts typical of the stainless-steel devices. SE and GRE imaging were very useful for determining caval patency in two patients with previously placed Mobin-Uddin filters. Noninvasive MR evaluation of blood vessels in the presence of a variety of low-artifact intravascular devices appears feasible.     

Large Molecule Specific Assay Operation: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team

The L2 Global Harmonization Team on large molecule specific assay operation for protein bioanalysis in support of pharmacokinetics focused on the following topics: setting up a balanced validation design, specificity testing, selectivity testing, dilutional linearity, hook effect, parallelism, and testing of robustness and ruggedness. The team additionally considered the impact of lipemia, hemolysis, and the presence of endogenous analyte on selectivity assessments as well as the occurrence of hook effect in study samples when no hook effect had been observed during pre-study validation.