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Download (.pdf) Valproic acid: Growth inhibition of head and neck cancer by induction of terminal differentiation and senescence
Background: There are limited studies on the effects of drugs that modulate epigenetic regulation for head and neck... more Background: There are limited studies on the effects of drugs that modulate epigenetic regulation for head and neck squamous cell carcinoma (HNSCC). This study determined the effect of valproic acid (VPA) on HNSCC. Methods: Growth inhibition effects of VPA alone or in combination with 5-aza-2'deoxycytidine (5-aza-dC) or all-trans retinoic acid (ATRA) was evaluated with MTT and clonogenic assays on 5 HNSCC cell lines. The mechanism of growth inhibition was investigated by looking at markers of terminal differentiation and senescence. Results: Growth inhibition profiles of HNSCC cell lines varied in response to VPA. Inhibition of clonogenic survival in response to VPA was associated with an upregulation of p21, expression of terminal differentiation markers, and cellular senescence. Notably, a combination treatment of 5-Aza-dC-VPA-ATRA enhanced growth inhibition in cells resistant to VPA. Conclusion: VPA is a potent inhibitor of proliferation in some HNSCC cell lines, and may be used to treat HNSCC.
Change and Aging: Senescence as an Adaptation
Understanding why we age is a long-lived open problem in evolutionary biology. Aging is prejudicial to the individual,... more
Understanding why we age is a long-lived open problem in evolutionary biology. Aging is prejudicial to the individual, and evolutionary forces should prevent it, but many species show signs of senescence as individuals age. Here, I will propose a model for aging based on assumptions that are compatible with evolutionary theory: i) competition is between individuals; ii) there is some degree of locality, so quite often competition will be between parents and their progeny; iii) optimal conditions are not stationary, and mutation helps each species to keep competitive. When conditions change, a senescent species can drive immortal competitors to extinction. This counter-intuitive result arises from the pruning caused by the death of elder individuals. When there is change and mutation, each generation is slightly better adapted to the new conditions, but some older individuals survive by chance. Senescence can eliminate those from the genetic pool. Even though individual selection forces can sometimes win over group selection ones, it is not exactly the individual that is selected but its lineage. While senescence damages the individuals and has an evolutionary cost, it has a benefit of its own. It allows each lineage to adapt faster to changing conditions. We age because the world changes.
Senescence patterns determined by species ranking on the fast-slow life-history continuum
by Owen Jones
Comparative analyses of survival senescence by using life tables have identified generalizations including the... more Comparative analyses of survival senescence by using life tables have identified generalizations including the observation that mammals senesce faster than similar-sized birds. These generalizations have been challenged because of limitations of life-table approaches and the growing appreciation that senescence is more than an increasing probability of death. Without using life tables, we examine senescence rates in annual individual fitness using 20 individual-based data sets of terrestrial vertebrates with contrasting life histories and body size. We find that senescence is widespread in the wild and equally likely to occur in survival and reproduction. Additionally, mammals senesce faster than birds because they have a faster life history for a given body size. By allowing us to disentangle the effects of two major fitness components our methods allow an assessment of the robustness of the prevalent life-table approach. Focusing on one aspect of life history – survival or recruitment – can provide reliable information on overall senescence.
Age-specific breeding success in a wild mammalian population: selection, constraint, restraint and senescence
Authors:
HANNAH L. DUGDALE
LISA C. POPE
CHRIS NEWMAN
DAVID W. MACDONALD
TERRY BURKE
Published in:
Molecular Ecology
The Selection, Constraint, Restraint and Senescence Hypotheses predict how breeding success should vary with age. The... more The Selection, Constraint, Restraint and Senescence Hypotheses predict how breeding success should vary with age. The Selection Hypothesis predicts between-individual variation arising from quality differences; the other hypotheses predict within-individual variation due to differing skills or physiological condition (Constraint), residual reproductive lifespan (Restraint), or somatic and reproductive investment (Senescence). Studies tend to focus on either the initial increase in breeding success or later decrease; however, both require consideration when unravelling the underlying evolutionary processes. Additionally, few studies present genetic fitness measures and rarely for both sexes. We therefore test these four hypotheses, which are not mutually exclusive, in a high-density population of European badgers Meles meles. Using an 18-year data set (including 22 microsatellite loci), we show an initial improvement in breeding success with age, followed by a later and steeper rate of reproductive senescence in male than in female badgers. Breeding success was skewed within age-classes, indicating the influence of factors other than age-class. This was partly attributable to selective appearance and disappearance of badgers (Selection Hypothesis). Individuals with a late age of last breeding showed a concave-down relationship between breeding success and experience (Constraint Hypothesis). There was no evidence of abrupt terminal effects; rather, individuals showed a concave-down relationship between breeding success and residual reproductive lifespan (Restraint Hypothesis), with an interaction with age of first breeding only in female badgers. Our results demonstrate the importance of investigating a comprehensive suite of factors in age-specific breeding success analyses, in both sexes, to fully understand evolutionary and population dynamics.
The evolution of social behaviour: the effect of mating system and social structure in the European badger Meles meles
Author:
Hannah L Dugdale
DPhil thesis. University of Oxford, Oxford. pp 282
Studies of mating systems and social organisation have been central to understanding of the evolution of social... more Studies of mating systems and social organisation have been central to understanding of the evolution of social behaviour. The European badger Meles meles is a good species in which to study these processes, as its complex social system provides an opportunity to investigate how both natural and kin selection shape the evolution of mating systems and social structure. In this thesis, I use behavioural and genetic data to describe the mating system and social organisation of a high-density badger population and examine the occurrence of cooperative breeding. I genotyped 915 (85%) badgers trapped in Wytham Woods (1987–2005), 630 of which were cubs, and assigned both parents to 331 cubs with 95% confidence. This revealed a polygynandrous mating system, with up to five mothers and five fathers per social group. Mounting behaviour was also polygynandrous and I show the strongest evidence to date for multiple-paternity litters. I demonstrate, for the first time, that groups consisted of close and distant kin: approximately one third of group members were first-order kin, and overall group members had slightly lower relatedness levels than half-siblings. Within groups, adult and yearling females had higher pairwise relatedness than males, and neighbouring groups contained relatives. These findings result from the high level (42%) of extra-group paternities, 86% of which were assigned to neighbouring males. For the first time I show that females avoided inbreeding by mating with extra-group males; however, incestuous matings did occur. Promiscuous and repeated mountings were observed, which may reduce male–male aggression and infanticide, but may also promote sperm competition, genetic diversity, and / or genetic compatibility. Just under a third of adult males and females were assigned parentage each year and I quantify, for the first time, reproductive skew within badger groups. Correlations between relatedness, group productivity, and reproductive skew were not consistent with the predictions of incomplete-control models; rather, resource availability may play a role. Older and younger badgers displayed reduced annual breeding success, with male success increasing initially with experience. The Restraint, Constraint, and Selection Hypotheses did not explain the age-related breeding pattern in females. Variance in lifetime breeding success (LBS) was greater for males. Males that only bred within or only outside of their groups had half the LBS of males that did both. Females that were assigned maternity probably bred cooperatively and allonursed non-offspring, which has not been demonstrated previously. No benefit was established, however, in terms of litter size, probability of offspring breeding, or offspring lifetime breeding success, with more mothers in a group. In conclusion, badger social groups are fostered through kinship ties. Polygynandry and repeated mounting may have evolved originally to reduce male–male aggression and infanticide by males, through paternity masking. Although plural breeding occurs, group living appears to be costly. Motivation to disperse may be reduced through high-levels of extra-group paternities, which may also reduce inbreeding. Cooperative breeding among mothers may represent a low-cost behaviour with indirect benefits due to high levels of relatedness between female group-members. Badger sociality therefore represents an early stage in the evolution of social behaviour.
Senescence of maize plants: evolution from flowering to harvest
In monocarpic species such as corn, senescence of leaves is coordinated with that of the whole plant and influenced by... more In monocarpic species such as corn, senescence of leaves is coordinated with that of the whole plant and influenced by the reproductive function. The objective of the present study was to describe the evolution of corn senescence along two axes: (1) the whole-plant axis, where all foliar stages were each considered as an entity, and (2) the foliar axis, where the dynamics of three macroscopic symptoms of senescence was considered on each leaf taken individually, according to zones from the apex to the base of the leaf lamina. From a corn field culture, leaves were sampled or whole plants were submitted to a follow-up, from flowering to harvest. Dynamics of water, dry matter, and chlorophyll contents were different along the leaf as well as between ranking of leaves. Moreover, plant chlorophyll content followed a more complex dynamics than that of water and dry matter. From a follow-up of discoloration along leaves of 15 stems from top to bottom, authors have established functional relationships describing the advance of the senescence front for each foliar rank from 7 to top (rank 15 or 16). This quantitative description can be used directly in crop models as well as structure-function plant models. This would allow estimation of leaf-senescence impact on light-radiation interception and, therefore, on photosynthesis and productivity. Results can also be used for interpretation of reflectance measurements on corn canopies by remote sensing.
Platelet Senescence and Death, 2007.
A review of platelet death. It is relatively well cited, considering...!!
Change and Aging: Senescence as an adaptation
Understanding why we age is a long-lived open problem in evolutionary biology. Aging is prejudicial to the individual... more
Understanding why we age is a long-lived open problem in evolutionary biology. Aging is prejudicial to the individual and evolutionary forces should prevent it, but many species show signs of senescence as individuals age. Here, I will propose a model for aging based on assumptions that are compatible with evolutionary theory: i) competition is between individuals; ii) there is some degree of locality, so quite often competition will between parents and their progeny; iii) optimal conditions are not stationary, mutation helps each species to keep competitive. When conditions change, a senescent species can drive immortal competitors to extinction. This counter-intuitive result arises from the pruning caused by the death of elder individuals. When there is change and mutation, each generation is slightly better adapted to the new conditions, but some older individuals survive by random chance. Senescence can eliminate those from the genetic pool. Even though individual selection forces always win over group selection ones, it is not exactly the individual that is selected, but its lineage. While senescence damages the individuals and has an evolutionary cost, it has a benefit of its own. It allows each lineage to adapt faster to changing conditions. We age because the world changes.
Resveratrol, but not dihydroresveratrol, induces premature senescence in primary human fibroblasts.
Faragher RG, Burton DG, Majecha P, Fong NS, Davis T, Sheerin A, Ostler EL.
Resveratrol, trans-3,5,4'-trihydroxystilbene, is a polyphenolic compound which has been reported to mimic the gene... more
Resveratrol, trans-3,5,4'-trihydroxystilbene, is a polyphenolic compound which has been reported to mimic the gene expression patterns seen in whole animals undergoing dietary restriction. The mechanism of action of resveratrol remains poorly understood, but modulation of both cellular proliferation and apoptosis has been proposed as important routes by which the molecule may exert its effects. This study reports the effects of both resveratrol and dihydroresveratrol (a primary in vivo metabolite) on the proliferative capacity of human primary fibroblasts. No generalised reduction in the growth fraction was observed when fibroblasts derived from three different tissues were treated with resveratrol at concentrations of 10 μm or less. However, concentrations above 25 μm produced a dose-dependent reduction in proliferation. This loss of the growth fraction was paralleled by an increase in the senescent fraction as determined by staining for senescence associated beta galactosidase and dose recovery studies conducted over a 7-day period. Entry into senescence in response to treatment with resveratrol could be blocked by a 30-min preincubation with the p38 MAP kinase inhibitor SB203580. No effects on proliferation were observed when cells were treated with dihydroresveratrol at concentrations of up to 100 μm.