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Biomedical subjects

Sarah Mathews

Publications and source records attributed to Sarah Mathews.

8 recordsLinked to original sources
PubMed2006

A phase II study of ZD6474 (Zactima, a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma--NCIC CTG IND.145.

Multiple myeloma is a disease in which angiogenesis is postulated to be a target for therapy. Based on this hypothesis, we conducted a phase II trial of ZD6474 (Zactima; a VEGFR inhibitor) 100 mg p.o. daily in patients with relapsed multiple myeloma. The primary efficacy endpoint was objective response as assessed by reduction in M protein. There were 18 patients with a mean age of 64 years. One patient was ineligible and one was not evaluable. Overall, ZD6474 was well tolerated and pharmacokinetic testing demonstrated that adequate drug levels were achieved. The most common drug-related adverse events were nausea, vomiting, fatigue, rash, pruritus, headache, diarrhea, dizziness, and sensory neuropathy, all of which were Grade I-II in severity. There were no drug-related serious adverse events. Laboratory adverse events were infrequent: one patient had Grade III anemia, and there were no Grade III changes in biochemistry. No significant QTc interval changes were seen. There were no responses in M protein levels. In conclusion, ZD6474 was well tolerated at a dose of 100 mg per day and achieved plasma levels predicted to inhibit VEGF signaling. However, this was not reflected in clinical benefit since none of the patients had a reduction in M protein.

Administration, Oral↗
PubMed2006

Phytochrome-mediated development in land plants: red light sensing evolves to meet the challenges of changing light environments.

Phytochromes are photoreceptors that provide plants with circadian, seasonal, and positional information critical for the control of germination, seedling development, shade avoidance, reproduction, dormancy, and sleep movements. Phytochromes are unique among photoreceptors in their capacity to interconvert between a red-absorbing form (absorption maximum of approximately 660 nm) and a far-red absorbing form (absorption maximum of approximately 730 nm), which occur in a dynamic equilibrium within plant cells, corresponding to the proportions of red and far-red energy in ambient light. Because pigments in stems and leaves absorb wavelengths below about 700 nm, this provides plants with an elegant system for detecting their position relative to other plants, with which the plants compete for light. Certain aspects of phytochrome-mediated development outside of flowering plants are strikingly similar to those that have been characterized in Arabidopsis thaliana and other angiosperms. However, early diverging land plants have fewer distinct phytochrome gene lineages, suggesting that both diversification and subfunctionalization have been important in the evolution of the phytochrome gene family. There is evidence that subfunctionalization proceeded by the partitioning among paralogues of photosensory specificity, physiological response modes, and light-regulated gene expression and protein stability. Parallel events of duplication and functional divergence may have coincided with the evolution of canopy shade and the increasing complexity of the light environment. Within angiosperms, patterns of functional divergence are clade-specific and the roles of phytochromes in A. thaliana change across environments, attesting to the evolutionary flexibility and contemporaneous plasticity of phytochrome signalling in the control of development.

Arabidopsis↗
PubMed2005

Analytical methods for studying the evolution of paralogs using duplicate gene datasets.

Gene duplication is widely viewed as an important source of raw material for functional innovation in proteins because at least some duplicate copies will evolve new or slightly modified functions. The study of the molecular processes by which functional innovation occurs interests both evolutionary biologists and protein chemists, and the development of methods to investigate these processes has led to a productive meeting of disciplines and an availability of complementary approaches for exploring datasets. This has resulted in insights into past events, prediction of current function, and prediction of future change. The methods fall broadly into two categories: those that rely on detection of shifts in selective constraints and those that rely on detection of correlations between molecular changes and functional shifts. Strengths and limitations of the methods are evaluated here in the context of the question being addressed, the input required, and the specific metric that is evaluated in each test.

Databases, Genetic↗
PubMed2003

Adaptive evolution in the photosensory domain of phytochrome A in early angiosperms.

Flowering plant diversity now far exceeds the combined diversity of all other plant groups. Recently identified extant remnants of the earliest-diverging lines suggest that the first angiosperms may have lived in shady, disturbed, and moist understory habitats, and that the aquatic habit also arose early. This would have required the capacity to begin life in dimly lit environments. If so, evolution in light-sensing mechanisms may have been crucial to their success. The photoreceptor phytochrome A is unique among angiosperm phytochromes in its capacity to serve a transient role under conditions where an extremely high sensitivity is required. We present evidence of altered functional constraints between phytochrome A (PHYA) and its paralog, PHYC. Tests for selection suggest that an elevation in nonsynonymous rates resulted from an episode of selection along the branch leading to all angiosperm PHYA sequences. Most nucleotide sites (95%) are selectively constrained, and the ratio of nonsynonymous to synonymous substitutions on branches within the PHYA clade does not differ from the ratio on the branches in the PHYC clade. Thus, positive selection at a handful of sites, rather than relaxation of selective constraints, apparently has played a major role in the evolution of the photosensory domain of phytochrome A. The episode of selection occurred very early in the history of flowering plants, suggesting that innovation in phyA may have given the first angiosperms some adaptive advantage.

Evolution, Molecular↗
PubMed2002

The root of the angiosperms revisited.

Most recent phylogenetic analyses of basal angiosperms have converged on the placement of Amborella as sister to all other extant angiosperms. However, certain recent studies suggest that Amborella and Nymphaeales (water lilies) form a clade sister to all remaining angiosperms or that Nymphaeales alone are the sister to the remaining angiosperms. We report here (i) maximum parsimony, maximum likelihood, and Bayesian phylogenetic analyses of 11 genes (>15,000 bp per taxon) for 16 taxa, (ii) maximum parsimony analysis for a subset of these genes for 104 taxa, and (iii) tests of alternative rootings with the nonparametric bootstrap and the likelihood ratio test with the parametric bootstrap. In addition, we use simulation analyses to examine the amount of bias that may be present in our methods of phylogeny estimation. Amborella continues to receive strong bootstrap support as the sister to all other extant angiosperms, and three of four tests reject alternative hypotheses of the angiosperm root. Although we cannot conclusively choose between Amborella vs. Amborella + Nymphaeales as sister to all other angiosperms, most analyses favor the former rooting.

Evolution, Molecular↗
PubMed2002

Laurasian migration explains Gondwanan disjunctions: evidence from Malpighiaceae.

Explanations for biogeographic disjunctions involving South America and Africa typically invoke vicariance of western Gondwanan biotas or long distance dispersal. These hypotheses are problematical because many groups originated and diversified well after the last known connection between Africa and South America (approximately 105 million years ago), and it is unlikely that "sweepstakes" dispersal accounts for many of these disjunctions. Phylogenetic analyses of the angiosperm clade Malpighiaceae, combined with fossil evidence and molecular divergence-time estimates, suggest an alternative hypothesis to account for such distributions. We propose that Malpighiaceae originated in northern South America, and that members of several clades repeatedly migrated into North America and subsequently moved via North Atlantic land connections into the Old World during episodes starting in the Eocene, when climates supported tropical forests. This Laurasian migration route may explain many other extant lineages that exhibit western Gondwanan distributions.

Arabidopsis Proteins↗
PubMed2002

Phylogeny of Acridocarpus-Brachylophon (Malpighiaceae): implications for tertiary tropical floras and Afroasian biogeography.

A major tenet of African Tertiary biogeography posits that lowland rainforest dominated much of Africa in the late Cretaceous and was replaced by xeric vegetation as a response to continental uplift and consequent widespread aridification beginning in the late Paleogene. The aridification of Africa is thought to have been a major factor in the extinction of many African humid-tropical lineages, and in the present-day disparity of species diversity between Africa and other tropical regions. This primarily geologically based model can be tested with independent phylogenetic evidence from widespread African plant groups containing both humid- and xeric-adapted species. We estimated the phylogeny and lineage divergence times within one such angiosperm group, the acridocarpoid clade (Malpighiaceae), with combined ITS, ndhF, and trnL-F data from 15 species that encompass the range of morphological and geographic variation within the group. Dispersal-vicariance analysis and divergence-time estimates suggest that the basal acridocarpoid divergence occurred between African and Southeast Asian lineages approximately 50 million years ago (mya), perhaps after a southward ancestral retreat from high-latitude tropical forests in response to intermittent Eocene cooling. Dispersion of Aeridocarpus from Africa to Madagascar is inferred between approximately 50 and 35 mya, when lowland humid tropical forest was nearly continuous between these landmasses. A single dispersal event within Acridocarpus is inferred from western Africa to eastern Africa between approximately 23 and 17 mya, coincident with the widespread replacement of humid forests by savannas in eastern Africa. Although the spread of xeric environments resulted in the extinction of many African plant groups, our data suggest that for others it provided an opportunity for further diversification.

Africa↗