PubMed Health⌕ Search

Biomedical subjects

R D Knight

Publications and source records attributed to R D Knight.

At least 19 recordsLinked to original sources
PubMed2006

Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide: phase I clinical trial of three dosing schedules in patients with solid malignancies.

Thalidomide is an anti-angiogenic agent currently used to treat patients with malignant cachexia or multiple myeloma. Lenalidomide (CC-5013) is an immunomodulatory thalidomide analogue licensed in the United States of America (USA) for the treatment of a subtype of myelodysplastic syndrome. This two-centre, open-label phase I study evaluated dose-limiting toxicities in 55 patients with malignant solid tumours refractory to standard chemotherapies. Lenalidomide capsules were consumed once daily for 12 weeks according to one of the following three schedules: (I) 25 mg daily for the first 7 d, the daily dose increased by 25 mg each week up to a maximum daily dose of 150 mg; (II) 25mg daily for 21 d followed by a 7-d rest period, the 4-week cycle repeated for 3 cycles; (III) 10 mg daily continuously. Twenty-six patients completed the study period. Two patients experienced a grade 3 hypersensitivity rash. Four patients in cohort I and 4 patients in cohort II suffered grade 3 or 4 neutropaenia. In 2 patients with predisposing medical factors, grade 3 cardiac dysrhythmia was recorded. Grade 1 neurotoxicity was detected in 6 patients. One complete and two partial radiological responses were measured by computed tomography scanning; 8 patients had stable disease after 12 weeks of treatment. Fifteen patients remained on treatment as named patients; 1 with metastatic melanoma remains in clinical remission 3.5 years from trial entry. This study indicates the tolerability and potential clinical efficacy of lenalidomide in patients with advanced solid tumours who have previously received multi-modality treatment. Depending on the extent of myelosuppressive pre-treatment, dose schedules (II) or (III) are advocated for large-scale trials of long-term administration.

Adult↗
PubMed2004

Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma.

PURPOSE: To assess the safety, efficacy, and immunomodulatory effects of CC-4047 (Actimid; Celgene, San Diego, CA) in patients with relapsed or refractory myeloma. PATIENTS AND METHODS: Twenty-four relapsed or refractory patients were treated with a dose-escalating regimen of oral CC-4047. Clinical responses and adverse effects were identified, and peripheral T-cell subsets, serum cytokines, and proangiogenic factors were evaluated. RESULTS: CC-4047 was tolerated with no serious nonhematologic adverse events. All patients were eligible for analysis. Toxicity criteria during the initial 4 weeks of study were used to define the maximum-tolerated dose (MTD). During this period, one patient withdrew with a deep vein thrombosis (DVT) probably caused by an undiagnosed primary melanoma with lymphadenopathy in the groin, one patient withdrew because of progressive disease (PD), and three patients discontinued with neutropenia. Nineteen of 24 patients continued on treatment beyond 4 weeks to PD or development of a serious adverse event. Three further patients developed a DVT at 4, 9, and 11 months. Treatment resulted in a greater than 25% reduction in paraprotein in 67% of patients, 13 patients (54%) experienced a greater than 50% reduction in paraprotein, and four (17%) of 24 patients entered complete remission. The MTD was 2 mg/d. All patients showed increased CD45RO expression on CD4(+) and CD8(+) cells, with a concomitant decrease in CD45RA(+) cells. CC-4047 treatment was associated with significantly increased serum interleukin (IL)-2 receptor and IL-12 levels, which is consistent with activation of T cells and monocytes and macrophages. CONCLUSION: This study demonstrates the safety and efficacy of CC-4047. The MTD of CC-4047 orally was 2 mg/d. This is the first report demonstrating in vivo T-cell costimulation by this class of compound, supporting a potential role for CC-4047 as an immunostimulatory adjuvant treatment.

Administration, Oral↗
PubMed2003

Protective effects of the urocortin homologues stresscopin (SCP) and stresscopin-related peptide (SRP) against hypoxia/reoxygenation injury in rat neonatal cardiomyocytes.

Urocortin (UCN), a member of the Corticotropin-Releasing Factor (CRF) family of peptides is a well described cardioprotective agent. UCN is able to bind to two types of G-protein coupled receptors: CRF receptor type 1 (CRFR1) and CRF receptor type 2 (CRFR2), whereas, two homologues of UCN, stresscopin (SCP) or also known as urocortin III (UCNIII) and stresscopin related peptide (SRP), or urocortin II (UCNII), bind exclusively and with high affinity to CRFR2, we hypothesised that they will exhibit more pronounced cardioprotective effects than UCN. We show for the first time that SCP is expressed in rat cardiomyocytes and that the levels of SRP and SCP are increased by hypoxic stress. All three peptides have potent cardioprotective effects in cells exposed to hypoxia/reoxygenation. When used at 10(-8) M they increased the amount of live cells by 25% when added prior to hypoxia, and by 20% when UCN and SCP were added at the onset of reoxygenation. In addition, the peptides are equally are more potent antiapoptotic factors than UCN. The antiapoptotic effects of SCP were more pronounced than SRP and UCN at a concentration of 10(-10) M. Furthermore, SCP and SRP protect cardiomyocytes better than UCN at concentrations up to and including 10(-10) M and reduced the amount of TUNEL positive cells almost by half at concentrations of 10(-12) to 10(-10) M. More importantly, we demonstrate that SCP and SRP are able to protect cardiomyocytes even if they are administered after the hypoxic insult and prior to reoxygenation. In this case SCP was more potent than UCN and SRP at 10(-12) M and both SCP and SRP exhibited higher protection at 10(-8) M compared to UCN. Cardioprotection of cardiomyocytes by 10(-8) M of peptides was abolished when treated with 50 microM LY294002 or 100 microM PD98059, but not by 10 microM SB203580 prior to the hypoxic insult. Transfection of dominant negative Akt and MEK1 also blocked protection by the peptides, whereas dominant negative MEKK6 had no effects, demonstrating that SCP and SRP, like UCN, require activation of p42/44 Mitogen activated protein kinase and Akt/Protein Kinase B in order to produce their cardioprotective effects. In addition, we showed that SCP and UCN are potent activators of the p42/44 MAPK pathway, with SRP able to induce phosphorylation of p42/44 MAPK as well, albeit not as pronounced.

Animals↗
PubMed2001

Origins of anteroposterior patterning and Hox gene regulation during chordate evolution.

All chordates share a basic body plan and many common features of early development. Anteroposterior (AP) regions of the vertebrate neural tube are specified by a combinatorial pattern of Hox gene expression that is conserved in urochordates and cephalochordates. Another primitive feature of Hox gene regulation in all chordates is a sensitivity to retinoic acid during embryogenesis, and recent developmental genetic studies have demonstrated the essential role for retinoid signalling in vertebrates. Two AP regions develop within the chordate neural tube during gastrulation: an anterior 'forebrain-midbrain' region specified by Otx genes and a posterior 'hindbrain-spinal cord' region specified by Hox genes. A third, intermediate region corresponding to the midbrain or midbrain-hindbrain boundary develops at around the same time in vertebrates, and comparative data suggest that this was also present in the chordate ancestor. Within the anterior part of the Hox-expressing domain, however, vertebrates appear to have evolved unique roles for segmentation genes, such as Krox-20, in patterning the hindbrain. Genetic approaches in mammals and zebrafish, coupled with molecular phylogenetic studies in ascidians, amphioxus and lampreys, promise to reveal how the complex mechanisms that specify the vertebrate body plan may have arisen from a relatively simple set of ancestral developmental components.

Animals↗
PubMed2001

Identification of conserved C2H2 zinc-finger gene families in the Bilateria.

BACKGROUND: Identification of orthologous relationships between genes from widely divergent taxa allows partial reconstruction of the gene complement of ancestral genomes. C2H2 zinc-finger genes are one of the largest and most complex gene superfamilies in metazoan genomes, with hundreds of members in the human genome. Here we analyze C2H2 zinc-finger genes from three taxa - Drosophila, Caenorhabditis elegans and human - from which near-complete genome sequence data are available. RESULTS: Our analyses conclusively identify 39 families of genes, of which 38 can be defined as orthology groups in that they are descended from single ancestral genes in the common ancestor of Drosophila, C. elegans and humans. CONCLUSIONS: On the basis of current metazoan phylogeny, these 39 groups represent the minimum complement of C2H2 zinc-finger genes present in the genome of the bilaterian common ancestor.

Animals↗
PubMed2001

A simple model based on mutation and selection explains trends in codon and amino-acid usage and GC composition within and across genomes.

BACKGROUND: Correlations between genome composition (in terms of GC content) and usage of particular codons and amino acids have been widely reported, but poorly explained. We show here that a simple model of processes acting at the nucleotide level explains codon usage across a large sample of species (311 bacteria, 28 archaea and 257 eukaryotes). The model quantitatively predicts responses (slope and intercept of the regression line on genome GC content) of individual codons and amino acids to genome composition. RESULTS: Codons respond to genome composition on the basis of their GC content relative to their synonyms (explaining 71-87% of the variance in response among the different codons, depending on measure). Amino-acid responses are determined by the mean GC content of their codons (explaining 71-79% of the variance). Similar trends hold for genes within a genome. Position-dependent selection for error minimization explains why individual bases respond differently to directional mutation pressure. CONCLUSIONS: Our model suggests that GC content drives codon usage (rather than the converse). It unifies a large body of empirical evidence concerning relationships between GC content and amino-acid or codon usage in disparate systems. The relationship between GC content and codon and amino-acid usage is ahistorical; it is replicated independently in the three domains of living organisms, reinforcing the idea that genes and genomes at mutation/selection equilibrium reproduce a unique relationship between nucleic acid and protein composition. Thus, the model may be useful in predicting amino-acid or nucleotide sequences in poorly characterized taxa.

Amino Acids↗
PubMed2001

The molecular basis of nuclear genetic code change in ciliates.

BACKGROUND: The nuclear genetic code has changed in several lineages of ciliates. These changes, UAR to glutamine and UGA to cysteine, imply that eukaryotic release factor 1 (eRF1), the protein that recognizes stop codons and terminates translation, changes specificity. Here we test whether changes in eRF1 drive genetic code evolution. RESULTS: Database sequence analysis reveals numerous genetic code alterations in ciliates, including UGA --> tryptophan in Blepharisma americanum and the distantly related Colpoda. We sequenced eRF1 from four ciliates: B. americanum, a heterotrich that independently derived the same eRF1 specificity as Euplotes, and three spirotrichs, Stylonychia lemnae, S. mytilus, and Oxytricha trifallax, that independently derived the same genetic code as Tetrahymena (UAR --> glutamine). Distantly related ciliates with similar codes show characteristic changes in eRF1. We used a sliding window analysis to test associations between changes in specific eRF1 residues and changes in the genetic code. The regions of eRF1 that display convergent substitutions are identical to those identified in a recently reported nonsense suppression mutant screen in yeast. CONCLUSIONS: Genetic code change by stop codon reassignment is surprisingly frequent in ciliates, with UGA --> tryptophan occurring twice independently. This is the first description of this code, previously found only in bacteria and mitochondria, in a eukaryotic nuclear genome. eRF1 has evolved strikingly convergently in lineages with variant genetic codes. The strong concordance with biochemical data indicates that our methodology may be generally useful for detecting molecular determinants of biochemical changes in evolution.

Amino Acid Sequence↗
PubMed2001

Rewiring the keyboard: evolvability of the genetic code.

The genetic code evolved in two distinct phases. First, the 'canonical' code emerged before the last universal ancestor; subsequently, this code diverged in numerous nuclear and organelle lineages. Here, we examine the distribution and causes of these secondary deviations from the canonical genetic code. The majority of non-standard codes arise from alterations in the tRNA, with most occurring by post-transcriptional modifications, such as base modification or RNA editing, rather than by substitutions within tRNA anticodons.

Animals↗
PubMed2001

Wave and place fixed DPOAE maps of the human ear.

Human intermodulation distortion product otoacoustic emissions (DPOAE) can be a mixture of low and high latency components. They have different level, phase, and suppression characteristics, which indicate that emissions arise both from the frequency region of the primary tones directly and indirectly via the DP frequency place. Which component dominates the measured DPOAE in the ear canal depends on the stimulus parameters, especially the frequency ratio, f2/f1. Interference between the two emissions adds complexity to measurements of DPOAE. The behavior and even existence of whichever emission route is lower in level often cannot directly be deduced from the raw DPOAE data because the other emission covers it. It is therefore not known whether both emissions are present for all stimulus parameters or whether the trends seen in each emission when they are the dominant emission route continue under stimulus conditions when they are not dominant. In this study, the two DPOAE components are separated by a post-processing method. Previously, maps of raw DPOAE data against f2/f1 and DP frequency have been obtained. To separate the components, sets of data consisting of f2/f1 sweeps were transformed by an inverse Fourier transform into the time domain. The low and high latency components appeared as two distinct peaks because of their different phase gradients. These peaks were separated by windowing in the time domain and two frequency domain maps were reconstructed, representing the low and high latency DPOAEs. It was found that the low latency component of the 2 f1-f2 DP was only emitted strongly with f2/f1 between approximately 1.1 and 1.3. The removal of the high latency component revealed the low ratio edge of this region, at which the level falls sharply. However, the low latency emission has been traced at reduced amplitude over a wide range of stimulus parameters. Although previously only observed at small frequency ratios, the high latency component was found to be present widely in the lower sideband, its level reducing slowly at larger f2/f1. Its phase behavior changes in the lower sideband, being approximately constant with DP frequency at small ratios of f2/f1, but deviating from this at wider ratios. These results support the hypothesis that a DPOAE component which propagates to and is re-emitted from the DP frequency place (place fixed emission) is present across a wide parameter range. However, for all but the close primary condition the lower sideband DPOAE is dominated by direct emission from the region of f2 and f1 wave interaction (wave fixed emission). A simple transmission line model is presented to illustrate how the observed DPOAE maps can arise on the basis of this hypothesis.

Cochlea↗
PubMed2000

Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials.

BACKGROUND: Pamidronate therapy previously has been shown to reduce skeletal complications effectively for up to 12 months in breast carcinoma patients with bone metastases. The current study data provide further follow-up results regarding the effects of long term (up to 24 months) pamidronate treatment in women with breast carcinoma and osteolytic metastases. METHODS: Follow-up results from two prospective, multicenter, randomized, double-blind, placebo-controlled intervention trials conducted at academic and community oncology centers were combined to provide a large data set with which to evaluate the long term efficacy and safety of pamidronate therapy. Seven hundred fifty-four women with Stage IV breast carcinoma and osteolytic metastases were randomized to the 2 treatment arms of the trial. Three patients were excluded from the intent-to-treat population for the analysis. A total of 751 evaluable patients were randomized to receive either a 90-mg intravenous pamidronate infusion (367 patients) or a placebo infusion (384 patients) every 3-4 weeks. The primary outcome measures were skeletal morbidity rate (events/year), proportion of patients developing a skeletal complication, and time to first skeletal complication. RESULTS: Of the 367 women receiving pamidronate, 115 (31.3%) completed the trial and 81 (22.1%) discontinued the study due to adverse events. Of the 384 women who received placebo, 100 (26.0%) completed the study and 76 (19.8%) discontinued the study due to adverse events. The skeletal morbidity rate was 2.4 in the pamidronate group and 3.7 in the placebo group (P < 0.001). In the pamidronate group, 186 of the 367 patients (51%) had skeletal complications compared with 246 of the 384 patients in the placebo group (64%) (P < 0.001). The median time to first skeletal complication was 12.7 months in the pamidronate group and 7 months in the placebo group (P < 0.001). Six patients treated with pamidronate discontinued treatment due to drug-related adverse events. Pain and analgesic scores were significantly worse in the placebo group compared with those patients in the pamidronate group. CONCLUSIONS: In the current study, monthly infusions of 90 mg of pamidronate as a supplement to antineoplastic therapy were found to be well tolerated and superior to antineoplastic therapy alone in preventing skeletal complications and palliating symptoms for at least 24 months in breast carcinoma patients with osteolytic bone metastases.

Aged↗
PubMed2000

An amphioxus Krox gene: insights into vertebrate hindbrain evolution.

The transcription factor Krox-20 has roles in the maintenance of segmentation and specification of segment identity in the vertebrate hindbrain. Overt hindbrain segmentation is a vertebrate novelty, and is not seen in invertebrate chordates such as amphioxus and tunicates. To test if the roles of Krox-20 are also derived, we cloned a Krox-20 related gene, AmphiKrox, from amphioxus. AmphiKrox is related to a small family of vertebrate Krox genes and is expressed in the most anterior region of the amphioxus brain and in the club shaped gland, a secretory organ that develops in the anterior pharynx. Neither expression domain overlaps with the expression of AmphiHox-1, -2, -3 or -4, suggesting that the roles of Krox-20 in hindbrain segmentation and in Hox gene regulation were acquired concomitant with the duplication of Krox genes in vertebrate evolution.

Amino Acid Sequence↗
PubMed2000

Guilt by association: the arginine case revisited.

If the genetic code arose in an RNA world, present codon assignments may reflect primordial RNA-amino acid affinities. Whether aptamers selected from random pools to bind free amino acids do so using the cognate codons at their binding sites has been controversial. Here we defend and extend our previous analysis of arginine binding sites, and propose a model for the maintenance of codon-amino acid interactions through the evolution of amino acids from ribozyme cofactors into the building blocks of proteins.

Anticodon↗
PubMed2000

Early fixation of an optimal genetic code.

The evolutionary forces that produced the canonical genetic code before the last universal ancestor remain obscure. One hypothesis is that the arrangement of amino acid/codon assignments results from selection to minimize the effects of errors (e.g., mistranslation and mutation) on resulting proteins. If amino acid similarity is measured as polarity, the canonical code does indeed outperform most theoretical alternatives. However, this finding does not hold for other amino acid properties, ignores plausible restrictions on possible code structure, and does not address the naturally occurring nonstandard genetic codes. Finally, other analyses have shown that significantly better code structures are possible. Here, we show that if theoretically possible code structures are limited to reflect plausible biological constraints, and amino acid similarity is quantified using empirical data of substitution frequencies, the canonical code is at or very close to a global optimum for error minimization across plausible parameter space. This result is robust to variation in the methods and assumptions of the analysis. Although significantly better codes do exist under some assumptions, they are extremely rare and thus consistent with reports of an adaptive code: previous analyses which suggest otherwise derive from a misleading metric. However, all extant, naturally occurring, secondarily derived, nonstandard genetic codes do appear less adaptive. The arrangement of amino acid assignments to the codons of the standard genetic code appears to be a direct product of natural selection for a system that minimizes the phenotypic impact of genetic error. Potential criticisms of previous analyses appear to be without substance. That known variants of the standard genetic code appear less adaptive suggests that different evolutionary factors predominated before and after fixation of the canonical code. While the evidence for an adaptive code is clear, the process by which the code achieved this optimization requires further attention.

Amino Acids↗
PubMed2000

Indications of different distortion product otoacoustic emission mechanisms from a detailed f1,f2 area study.

The primary site of generation on the basilar membrane for the 2f1-f2 distortion product (DP) is generally considered to be near where the higher-frequency stimulus tone peaks. This site has also been shown to be a source of DP otoacoustic emission (DPOAE) in the ear canal, but a second source of emission is known to exist in the region of the DP frequency place. The DPOAE phase versus frequency gradient provides a means of investigating the emission mechanisms. "Wave-fixed" and "place-fixed" mechanisms have been proposed to account for the very different phase gradients found depending on whether the 2f1-f2 DPOAE is evoked by a small or large stimulus-frequency ratio. DPOAE phase versus frequency gradients can be investigated either by sweeping f1,f2 or by sweeping both frequencies maintaining a constant frequency ratio. Each manipulation gives only a partial description of DP behavior. In this study, the place-fixed/ wave-fixed dichotomy is analyzed using extensive 2f1-f2 and 2f2-f1 DP stimulus-frequency sweep data presented on matrices of f1 vs f2 and f2/f1 ratio versus DP frequency. These show how the DPs are related and provide a more complete picture of 2 f1-f2 and 2f2-f1 DPOAE phase and amplitude versus frequency behavior. The phase data contain evidence for a systematic variation in the proportions of wave- and place-fixed emission. The results suggest that 2f1-f2 DPOAEs with a wide stimulus frequency ratio are wave fixed, while all other DPOAEs are place fixed. A transition occurs within the 2 f1-f2 DP data region at a frequency ratio of about f2/f1 = 1.1. The 2f1-f2 DP and 2 f2-f1 DP phase behavior is continuous across the f2/f1 = 1 boundary. As the 2 f2-f1 DP generation region must be strongly influenced by the DP frequency place, the results imply that the place-fixed component of the 2 f1-f2 DP is also linked to its frequency place. A similar pattern was obtained with the 3f1-2f2 and 3f2-2f1 DPs. The results support the following model: For the limited set of stimulus conditions that gives rise to 2 f1-f2 wave-fixed emissions, DP energy is largely generated in the f2 region and is emitted directly. All other DPOAEs are place-fixed emissions, and while nonlinearity within the f2 stimulus envelope remains the generator, the DP is not directly emitted but travels apically until it is re-emitted basally via a separate reflection mechanism in the region of the DP place.

Adult↗