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Biomedical subjects

J J Wright

Publications and source records attributed to J J Wright.

At least 19 recordsLinked to original sources
PubMed2001

Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial.

R115777 is a nonpeptidomimetic enzyme-specific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration. Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias. The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity. (Blood. 2001;97:3361-3369)

Adult↗
PubMed2001

Prediction of electroencephalographic spectra from neurophysiology.

A recent neurophysical model of propagation of electrical waves in the cortex is extended to include a physiologically motivated subcortical feedback loop via the thalamus. The electroencephalographic spectrum when the system is driven by white noise is then calculated analytically in terms of physiological parameters, including the effects of filtering of signals by the cerebrospinal fluid, skull, and scalp. The spectral power at low frequencies is found to vary as f(-1) when awake and f(-3) when asleep, with a breakpoint to a steeper power-law tail at frequencies above about 20 Hz in both cases; the f(-1) range concurs with recent magnetoencephalographic observations of such a regime. Parameter sensitivities are explored, enabling a model with fewer free parameters to be proposed, and showing that spectra predicted for physiologically reasonable parameter values strongly resemble those observed in the laboratory. Alpha and beta peaks seen near 10 Hz and twice that frequency, respectively, in the relaxed wakeful state are generated via subcortical feedback in this model, thereby leading to predictions of their frequencies in terms of physiological parameters, and of correlations in their occurrence. Subcortical feedback is also predicted to be responsible for production of anticorrelated peaks in deep sleep states that correspond to the occurrence of theta rhythm at around half the alpha frequency and sleep spindles at 3/2 times the alpha frequency. An additional positively correlated waking peak near three times the alpha frequency is also predicted and tentatively observed, as are two new types of sleep spindle near 5/2 and 7/2 times the alpha frequency, and anticorrelated with alpha. These results provide a theoretical basis for the conventional division of EEG spectra into frequency bands, but imply that the exact bounds of these bands depend on the individual. Three types of potential instability are found: one at zero frequency, another in the theta band at around half the alpha frequency, and a third at the alpha frequency itself.

Adult↗
PubMed2001

Novel mimics of sialyl Lewis X: design, synthesis and biological activity of a series of 2- and 3-malonate substituted galactoconjugates.

A series of potent inhibitors of P-selectin as potential anti-inflammatory agents is reported. These compounds are derivatives of galactocerebrosides bearing a malonate side chain in positions 2 and 3 of the galactose moiety. Based on the binding mode of sialyl Lewis X, the two acidic groups of the malonate are designed to form ionic interactions with two important lysines in the active site of P-selectin, Lys113 and Lys111. On the other hand, the 4- and 6-hydroxy groups on the galactose ring are arranged to chelate the calcium ion in the P-selectin active site. The synthesis and the biological activity of this series of compounds are described. Lead compounds having a greater potency than sialyl Lewis X are identified.

Animals↗
PubMed2001

Physical interaction between p53 and primary response gene Egr-1.

The tumor suppressor p53 and primary response gene Egr-1 are nuclear transcription factors with regulatory roles in signal transduction pathways mediating cellular proliferation and growth arrest as well as the complex genetic programs controlling differentiation and programmed cell death. We identified a physical association between these regulatory proteins in vitro and in vivo. Recombinant p53 and Egr-1 fusion proteins complexed with in vitro translates of Egr-1 or p53, respectively, or with these respective proteins in cell lysates. This protein-protein interaction was detected in vivo by immunoprecipitation and Western blot analysis of serum-activated cellular lysates with high levels of induced Egr-1 and of human lung cancer cell lines with constitutive overexpression of Egr-1 and mutant p53. A p53 mutant at codon 154 did not bind Egr-1, while p53 proteins with point mutations at residues 156, 246, 247, and 273 associated with this zinc finger transcription factor. p53 bound full-length Egr-1 and an Egr-1 mutant with a deletion of the 5' transactivation region but did not associate with Egr-1 protein lacking an internal segment that included the first two zinc finger domains, suggesting that binding may require the presence of intact zinc finger motifs. A variant-sized Egr-1 protein expressed by lung fibroblast cell line MRC-9 was also bound by p53. The interaction of these regulatory proteins may alter multiple features of their biological activity especially with regard to the specificity of transcriptional control.

Blotting, Western↗
PubMed2001

A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer.

PURPOSE: Flavopiridol is a potent cyclin-dependent kinase inhibitor with preclinical activity against non-small cell lung cancer (NSCLC), inhibiting tumor growth in vitro and in vivo by cytostatic and cytotoxic mechanisms. A Phase II trial was conducted to determine the activity and toxicity of flavopiridol in untreated patients with metastatic NSCLC. EXPERIMENTAL DESIGN: A total of 20 patients were treated with a 72-h continuous infusion of flavopiridol every 14 days at a dose of 50 mg/m(2)/day and a concentration of 0.1-0.2 mg/ml. Dose escalation to 60 mg/m(2)/day was permitted if no significant toxicity occurred. Response was initially assessed after every two infusions; patients treated longer than 8 weeks were then assessed after every four infusions. Plasma levels of flavopiridol were measured daily during the first two infusions to determine steady-state concentrations. RESULTS: This study was designed to evaluate a total of 45 patients in two stages. However, because no objective responses were seen in the first 20 patients, the early-stopping rule was invoked, and patient accrual was halted. In four patients who received eight infusions, progression was documented at 15, 20, 40, and 65 weeks, respectively. The most common toxicities included grade 1 or 2 diarrhea in 11 patients, asthenia in 10 patients, and venous thromboses in 7 patients. The mean +/- SD steady-state concentration of drug during the first infusion was 200 +/- 89.9 nM, sufficient for cytostatic effects in in vitro models. CONCLUSIONS: At the current doses and schedule, flavopiridol does not have cytotoxic activity in NSCLC, although protracted periods of disease stability were observed with an acceptable degree of toxicity.

Aged↗
PubMed2000

Mechanisms of cortical electrical activity and emergence of gamma rhythm.

A continuum model of the electrical activity of the cerebral cortex is described which predicts the occurrence of a resonance in the gamma range near 40 Hz. The emergence of this resonance is due to two refinements to a previous model, namely the inclusion of a modulation of synaptic strength due to finite reversal potentials, and use of parameters that better match physiological measurements. Analytical expressions for the fixed points of the system and for its linear dynamics are found in terms of average neuronal properties, and together explain the occurrence and modulation of the gamma-like resonance. The analytical results are confirmed by a numerical simulation.

Cerebral Cortex↗
PubMed2000

Synchronous cortical gamma-band activity in task-relevant cognition.

Widespread synchronous oscillatory activity, particularly in the gamma ('40 Hz') band, has been postulated to exist in the brain as a mechanism underlying binding. A new method of examining phase synchronicity across multiple electrode sites in specific EEG frequency bands as a function of time was employed, in a conventional cognitive ERP paradigm in 40 normal subjects. A significant late post-stimulus gamma synchronicity response occurred for task-relevant stimuli, whereas for task-irrelevant stimuli no such response was evident. However, an early response was seen for both task-relevant and irrelevant stimuli. This is the first empirical demonstration that widespread synchronous high frequency oscillations occur in humans in relation to cognition.

Acoustic Stimulation↗
PubMed2000

Synchronous oscillation in the cerebral cortex and object coherence: simulation of basic electrophysiological findings.

A lumped continuum model for electrocortical activity was used to simulate several established experimental findings of synchronous oscillation which have not all been previously embodied in a single explanatory model. Moving-bar visual stimuli of different extension, stimuli moving in different directions, the impact of non-specific cortical activation upon synchronous oscillation, and the frequency content of EEG associated with synchrony were considered. The magnitude of zero lag synchrony was primarily accounted for by the properties of the eigenmodes of the travelling local field potential superposition waves generated by inputs to the cortex, largely independent of the oscillation properties and associated spectral content. Approximation of the differences in cross-correlation observed with differently moving bar stimuli, and of the impact of cortical activation, required added assumptions on (a) spatial coherence of afferent volleys arising from parts of a single stimulus object and (b) the presence of low-amplitude diffuse field noise, with enhancement of cortical signal/noise ratio with respect to the spatially coherent inputs, at higher levels of cortical activation. Synchrony appears to be a ubiquitous property of cortex-like delay networks. Precision in the modelling of synchronous oscillation findings will require detailed description of input pathways, cortical connectivity, cortical stability, and aspects of cortical/subcortical interactions.

Artifacts↗
PubMed2000

Novel marine-derived anticancer agents: a phase I clinical, pharmacological, and pharmacodynamic study of dolastatin 10 (NSC 376128) in patients with advanced solid tumors.

Dolastatin (DOLA)-10 is a pentapeptide isolated from the mollusc Dolabella auricularia with clinically promising antitumor activity documented in various in vitro and in vivo tumor models. The objectives of this Phase I study were to determine the maximum tolerated dose, evaluate toxic effects, and document any antitumor activity of this novel agent. Using an electrospray ionization mass spectroscopy system, we also characterized the clinical pharmacokinetics, pharmacodynamics, and metabolism of DOLA-10. The maximum tolerated dose was reached at 300 microg/m2. Granulocytopenia, the dose-limiting toxicity, was documented in 33% of the patients treated at that dose level. There were no episodes of thrombocytopenia or severe anemia (Hgb < 8), and no major nonhematological toxicity was observed. Stabilization of tumor growth was observed in four patients, but no objective responses were seen. Whereas a two-compartment model described the DOLA-10 plasma concentration-time data reasonably well, a three-compartment model consistently performed better. After a rapid distribution phase, DOLA-10 plasma levels declined with mean beta and gamma half-lives of 0.99 and 18.9 h, respectively. Significant interpatient and intrapatient variability in DOLA-10 plasma clearances was observed. The mean area under the concentration-time curve increased proportionally as the dose was escalated, but there was significant overlap between dose levels. The area under the concentration-time curve and the percentage of decline in neutrophils were correlated. A single DOLA-10 metabolite was detected in five patients. Unlike the in vitro studies of DOLA-10, the principal metabolite detected was an N-demethyl derivative, confirmed by mass spectroscopy. In all five subjects, the concentration of this metabolite never exceeded 2% of the simultaneously measured parent drug concentration. The available preclinical, pharmacological, and clinical data suggest that further study of escalated DOLA-10 dosing with cytokine support is warranted.

Adult↗
PubMed2000

Molecular heterogeneity and function of EWS-WT1 fusion transcripts in desmoplastic small round cell tumors.

Desmoplastic small round cell tumor (DSRCT) is a primitive sarcoma with a consistent cytogenetic abnormality, t(11;22)(p13;q12). This chromosomal translocation generates a chimeric transcript that is formed by fusion of the 5' region of the Ewing's sarcoma gene, EWS, with the 3' DNA-binding segment of WT1, the Wilms' tumor suppressor gene. We collected 14 DSRCT tumor samples and examined the hybrid transcripts. We identified: (a) combinatorial heterogeneity of EWS exons fused to WT1 including use of EWS exons 7, 8, and 9; (b) subpopulations of variant transcripts in 6 of 14 tumors characterized by aberrant splicing resulting in loss of EWS exon 6 or WT1 exon 9; (c) multiple cDNA products with large internal deletions; and (d) insertion of small stretches of heterologous DNA at the fusion site or exon splice region in transcripts from two tumors. Most of the splice variants were in-frame, and in vitro translated fusion proteins with intact DNA-binding motifs formed complexes with a WT1 response element in gel mobility assays. Each of the chimeric proteins retains the ability to bind to the GC and TC elements of the early transcription factor EGR-1 as well as WT1 consensus sequences. We present evidence that various EWS-WT1 proteins up-regulated EGR-1 promoter activity and that this up-regulation is specifically dependent upon the absence of the exon 9 KTS domain of WT1. The molecular diversity and functionality exhibited by these fusion transcripts may have significant biological implications for their transactivating and tumorigenic potential.

Abdominal Neoplasms↗
PubMed1999

Simulation of EEG: dynamic changes in synaptic efficacy, cerebral rhythms, and dissipative and generative activity in cortex.

A simulation of electrocortical activity based upon coupled local aggregates of excitatory and inhibitory cells was modified to include rapid dynamic variations of synaptic efficacy attributable to reversal potentials and related effects. The modified simulation reproduces the rhythmic phenomena observed in real EEG, including the theta, alpha, beta and gamma rhythms, in association with physiologically realistic pulse densities. At high levels of cortical activation, generative activity with a 40-Hz center frequency emerges, suggesting a basis for the occurrence of phase changes and "edge of chaos" dynamics. These local oscillation properties complement the dissipative travelling wave and synchronous oscillation effects attributable to longer range excitatory couplings, as previously demonstrated in related simulations. Results of variation of parameters provide a first approximation to the anticipated effects of slow physiological time variations in gains and lags, and some predictions of the model are described.

Animals↗
PubMed1999

Alpha rhythm emerges from large-scale networks of realistically coupled multicompartmental model cortical neurons.

Conical pyramidal and stellate neurons were simulated using the GENESIS simulation package. Model neurons were leaky integrate-and-fire and consisted of from four to nine passive compartments. Neurophysiological measurements, based on single-cell recordings and patch-clamp experiments, provided estimations for the simulation of cortical neurons: transmitter-activated conductances, passive membrane time constants and axonal delays. Network connectivity was generated using a previously described probabilistic scheme based on known cortical histology, in which the probability of connections forming between one neuron and another fell off monotonically with increasing inter-cellular separation. Simulations of up to 6400 cortical neurons, approaching the scale of an individual cortical column, confirmed previous findings with smaller networks. Limit-cycle behaviour emerged in the network, in the frequency in the range of the mammalian alpha and beta rhythms (8-20 Hz). Contrary to expectation, near-linear relationships were found between the mean soma membrane potential and and neuronal firing probability. Some of the implications for cortical information processing, in particular the dynamical interactions between the neuronal and larger scales, are discussed.

Alpha Rhythm↗
PubMed1999

Dynamics of SCR, EEG, and ERP activity in an oddball paradigm with short interstimulus intervals.

Studies of concurrent central, and autonomic activity using a conventional event-related potential (ERP) oddball paradigms, are considered useful in elucidating the relationship between central and autonomic responses, but the autonomic response tends to overlap. A new method was used to decompose and score overlapping skin conductance responses (SCR). This method enabled examination of dynamic relationships of phasic SCR, prestimulus electroencephalogram (EEG), and ERP to auditory target stimuli in 50 normal adults. SCR amplitude was negatively correlated to EEG and N200 amplitude. The SCR amplitude changes over time exhibited an exponential decline opposite to those of N200, alpha, and beta. All the fitted exponential functions had a time constant of 1-2 min. The findings suggest that a N200 component, active in the auditory sensory discrimination, is concomitant with the SCR. The narrow range of the time constant may provide a clue to the conjoint processes underlying central and autonomic adaptive functions.

Adult↗
PubMed1999

Inter-relationships between small, dense low-density lipoprotein (LDL), plasma triacylglycerol and LDL apoprotein B in an atherogenic lipoprotein phenotype in free-living subjects.

A predominance of small, dense low-density lipoprotein (LDL) is a major component of an atherogenic lipoprotein phenotype, and a common, but modifiable, source of increased risk for coronary heart disease in the free-living population. While much of the atherogenicity of small, dense LDL is known to arise from its structural properties, the extent to which an increase in the number of small, dense LDL particles (hyper-apoprotein B) contributes to this risk of coronary heart disease is currently unknown. This study reports a method for the recruitment of free-living individuals with an atherogenic lipoprotein phenotype for a fish-oil intervention trial, and critically evaluates the relationship between LDL particle number and the predominance of small, dense LDL. In this group, volunteers were selected through local general practices on the basis of a moderately raised plasma triacylglycerol (triglyceride) level (>1.5 mmol/l) and a low concentration of high-density-lipoprotein cholesterol (<1.1 mmol/l). The screening of LDL subclasses revealed a predominance of small, dense LDL (LDL subclass pattern B) in 62% of the cohort. As expected, subjects with LDL subclass pattern B were characterized by higher plasma triacylglycerol and lower high-density lipoprotein cholesterol (<1.1 mmol/l) levels and, less predictably, by lower LDL cholesterol and apoprotein B levels (P<0.05; LDL subclass A compared with subclass B). While hyper-apoprotein B was detected in only five subjects, the relative percentage of small, dense LDL-III in subjects with subclass B showed an inverse relationship with LDL apoprotein B (r=-0.57; P<0.001), identifying a subset of individuals with plasma triacylglycerol above 2.5 mmol/l and a low concentration of LDL almost exclusively in a small and dense form. These findings indicate that a predominance of small, dense LDL and hyper-apoprotein B do not always co-exist in free-living groups. Moreover, if coronary risk increases with increasing LDL particle number, these results imply that the risk arising from a predominance of small, dense LDL may actually be reduced in certain cases when plasma triacylglycerol exceeds 2.5 mmol/l.

Adult↗
PubMed1998

Steady state visually evoked potential correlates of auditory hallucinations in schizophrenia.

This study attempted to localize regions of brain electrical activity associated with the onset of auditory hallucinations. Changes in Steady State Visually Evoked Potential (SSVEP) topography associated with the onset of spontaneous auditory hallucinations was studied in eight schizophrenic patients. The SSVEP elicited by a spatially uniform sinusoidally varying visual flicker was recorded using a 64-channel electrode helmet. A large and significant decrease in SSVEP latency in the right temporo/parietal region occurred in the second prior to the report of auditory hallucinations. A control task with matching motor movements produced no significant decrease in SSVEP latency in the same right temporo/parietal location. This finding suggests that activity of fine temporal resolution in the neural networks in the right temporo/parietal area may be implicated in the genesis of auditory hallucination, in conformity with certain neuropsychological theories.

Adult↗
PubMed1997

Sulfated galactocerebrosides as potential antiinflammatory agents.

Native sulfatides, as well as many sulfated glycolipids, have been shown to avidly bind to the selectin receptors. In vivo, native sulfatides significantly block activity in selectin-dependent inflammatory responses. The fact that nonsulfated galactocerebrosides did not inhibit selectin-mediated adhesion identified a critical role for the anionic sulfate residue. We therefore initiated a program to evaluate the activity of position isomers. This study showed a binding selectivity for the positions 2 and 3 of the sulfate group on the carbohydrate ring as well as enhanced activity for the disulfated analogs. Furthermore, it was discovered that the attachment of lipophilic substituents on the carbohydrate ring was tolerated, consistent with the presence of a lipophilic pocket in the binding activity. This resulted in compounds with a 6-fold increased potency.

Animals↗