Increased expression of fibroblast growth factors (FGFs) and their receptor by protamine and suramin on Kaposi's sarcoma-derived cells

Growth factors, such as bFGF, have been shown to exert autocrine and paracrine effects on the growth of Kaposi's Sarcoma (KS)-derived cells, which suggested that the inhibitors of angiogenesis may be promising for KS treatment. However, KS lesions have been found to continue to enlarge after patients had been treated with FGF binding antagonists such as suramin. We investigated the effect of protamine and suramine on the growth of KS derived cells in vitro. Although both of these agents which are FGF binding antagonists were found to inhibit the incorporation of 3H thymidine in KS-derived cultured cells, increased expression of bFGF, FGF5 and the FGF receptor was observed after the KS cells were exposed to these substances. These results might explain the clinical observation that FGF binding antagonists such as suramin caused an apparent stimulation of KS tumor growth when administered systemically to patients with AIDS-related KS.     

Identifying psychophysiological risk for psychopathology: examples from substance abuse and schizophrenia research

A problem confronting the search for psychopathology-related genes concerns the difficulty identifying gene carriers. Psychiatric diagnosis provides imperfect identification of affected individuals, and unaffected gene carriers go undetected. Psychophysiological measures may assist molecular genetic investigations by indicating genetic susceptibility for psychopathology, thus increasing the probability of identifying affected and unaffected gene carriers. Research strategies based on these premises are applied to the study of psychoactive substance use disorders and schizophrenia. Data are presented illustrating (1) that individual differences in inhibitory control involving autonomic and antisaccade eye movement measures and the P3 component of the event-related potential may be sensitive to susceptibility for substance use disorders, and (2) that eye tracking variables may identify genetic risk for schizophrenia.     

Use of cumulative meta-analysis in the design, monitoring, and final analysis of a clinical trial: a case study

From 1983 to 1987, the Department of Veterans Affairs (DVA) Cooperative Studies Program (CSP) conducted a multicenter clinical trial (CSP #207) to determine whether four different antiplatelet regimens compared to placebo could prevent the occlusion of grafts following coronary artery bypass surgery. The study showed that all of the active regimens tended to be better than placebo and that the three regimens containing aspirin were statistically significantly better. A cumulative meta-analysis of 12 trials performed shortly before the end of CSP #207 raised the issue as to whether the meta-analysis, if done earlier, would have changed the conduct of the trial. At the start of the planning period, one trail of size n = 37 had been published with a nonsignificant odds ratio (OR) of 0.74 (95% CI: 0.18, 3.12). At the time that CSP # 207 was approved by the DVA Cooperative Studies Evaluation Committee, two trials had been published (cumulative n = 150, OR = 0.44, 95% CI 0.19, 0.99). At the time patient intake started, five trials showed cumulative n = 769, OR = 0.42, 95% CI = 0.26, 0.68. Although the first 6-month CSP #207 progress report showed no treatment effect, by the time of the 12-month review by the Data Monitoring Board (DMB) a trend was developing in favor of active treatment. If the results of the meta-analysis had been available to the DMB at that time, conceivably the Board would have recommended stopping the placebo arm because of a convincing treatment effect based on the totality of the evidence. Cumulative meta-analysis could be useful as an adjunct in the planning, conduct, and final analysis of a clinical trial. It could also be used as one piece of evidence in the monitoring of the ongoing phase of a trial.     

Regulation of NMDA receptor phosphorylation by alternative splicing of the C-terminal domain

The NMDA (N-methyl D-aspartate) receptors in the brain play a critical role in synaptic plasticity, synaptogenesis and excitotoxicity. Molecular cloning has demonstrated that NMDA receptors consist of several homologous subunits (NMDAR1, 2A-2D). A variety of studies have suggested that protein phosphorylation of NMDA receptors may regulate their function and play a role in many forms of synaptic plasticity such as long-term potentiation. We have examined the phosphorylation of the NMDA receptor subunit NMDAR1 (NR1) by protein kinase C (PKC) in cells transiently expressing recombinant NR1 and in primary cultures of cortical neurons. PKC phosphorylation occurs on several distinct sites on the NR1 subunit. Most of these sites are contained within a single alternatively spliced exon in the C-terminal domain, which has previously been proposed to be on the extracellular side of the membrane. These results demonstrate that alternative splicing of the NR1 messenger RNA regulates its phosphorylation by PKC, and that mRNA splicing is a novel mechanism for regulating the sensitivity of glutamate receptors to protein phosphorylation. These results also provide evidence that the C-terminal domain of the NR1 protein is located intracellularly, suggesting that the proposed transmembrane topology model for glutamate receptors may be incorrect.