High frequency of N-ras activation in acute myelogenous leukemia

Using the NIH/3T3 cell transfection assay, activated cellular oncogenes have been detected in around 10% to 20% of human tumors. From a series of DNA preparations from tissues infiltrated with acute myelogenous leukemia (AML), 50% (3/6) caused transformation of NIH/3T3 cells. Thus AML appears to be the human tumor with the highest frequency of oncogenes detected by DNA transfection. In each case the oncogene involved was N-ras, a member of the ras gene family. Biologic and clinical parameters of AML patients with and without N-ras oncogenes in their tumors are discussed.     

Expression of cell surface receptors and oxidative metabolism modulation in the clinical continuum of sepsis

Background  

Infection control depends on adequate microbe recognition and cell activation, yet inflammatory response may lead to organ dysfunction in sepsis. The aims of this study were to evaluate cell activation in the context of sepsis and its correlation with organ dysfunction.     

持续腰池脑脊液引流治疗隐球菌性脑膜炎的临床探讨

0引言 隐球菌性脑膜炎(隐脑)是由隐球菌属中某些种或变种侵犯中枢神经系统引起的一种深部真菌病. 隐脑在我国仍以散发为主,近年来发病呈明显上升的趋势;而在一些发展中国家,AIDS患者隐脑的发病率更高[1]. 隐脑的误诊率较高,其治疗中存在较多问题,因为在现有的抗真菌治疗条件下,国内外文献报道其病死率仍高达25%～60%[1]. 现将我科1997-01/2005-01收治的19例中,进行了持续腰池脑脊液(CSF)引流的9例隐球菌脑膜炎患者与对照组10例观察报告如下,探讨有效的治疗手段.     

Effects of gender and age on paediatric headache

The aim of this study was to evaluate the impact of gender and age on headache characteristics and disability. Headache characteristics were assessed at an initial visit to a paediatric specialty care centre and five follow-up visits. A total number of 4121 patients were evaluated. Fifty-eight per cent of the sample was female. Boys were younger at their first headache and initial visit. They more frequently described headache pain as squeezing and location as top of the head. Girls reported more frequent and longer headaches. Girls more often described headache pain as sharp and location as back of the head. Age accounted for more variance than gender in headache severity, duration, frequency and disability. Gender differences exist in headache characteristics. Age is also an important factor in the variability in characteristics and disability. Longitudinal studies are needed to describe further the natural history of headaches in childhood and compare outcome between genders.     

Interaction of deoxyguanosine nucleotide analogs with human telomerase

To maintain the telomeres at the ends of the chromosomes, telomerase in human cells adds a repeating sequence of nucleotides (TTAGGG) to the 3'-end of each chromosome using an RNA component of the enzyme as the template for DNA synthesis. Because of the selective expression of this enzyme in cancer cells, we have evaluated the interaction of human telomerase with several deoxyguanosine nucleotides of clinical importance. 2',3'-dideoxyguanosine 5'-triphosphate, 6-thio-2'-deoxyguanosine 5'-triphosphate (T-dGTP), carbovir 5'-triphosphate, and D-carbocyclic-2'-deoxyguanosine 5'-triphosphate (D-CdG-TP) inhibited telomerase activity by 50% when these analogs were present at only 2 to 9 times the dGTP concentration. The L-enantiomer of CdG-TP was far less inhibitory, thereby demonstrating the stereoselectivity of telomerase for nucleotide substrates. T-dGTP was incorporated into the DNA by telomerase in the absence of dGTP, but unlike dGTP there was little extension of the DNA chain after its incorporation. These results indicate that the metabolites of three clinically useful agents (6-mercaptopurine, 6-thioguanine, and Abacavir) can inhibit human telomerase activity, and it is possible that the effect of these nucleotides on telomerase activity or telomere function could contribute to the mechanism of action of these agents.     

How Modeling and Simulation Have Enhanced Decision Making in New Drug Development

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer’s disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the “Learn-Confirm” paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled “Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products” made this scientific approach to the drug approval process possible.