Malignant cells are known to have elevated rates of mevalonate synthesis because of increased levels and catalytic efficiency of 3-hydroxy-3-methylglutaryl-CoA reductase. Whether this increased ...mevalonate synthesis occurs as a consequence of increased requirements for a mevalonate-derived metabolite in response to rapid growth or whether mevalonate promotes the growth of tumor cells is unknown. To address this question, we administered mevalonate via miniosmotic pumps to nude mice inoculated with MDA-MB-435 human cancer cells. After 13 weeks of growth, tumors in mevalonate-treated mice were significantly larger than tumors in saline-treated, control mice (1.52 ± 0.26 g versus 0.81 ± 0.27 g respectively, p < 0.05). The cancer cells treated in culture with mevalonate also demonstrated increased proliferation rates associated with accelerated entry of cells into S phase. These cells had enhanced total and cyclin A-immunoprecipitable cyclin-dependent kinase-2 (CDK-2) activity, increased activating phosphorylation of CDK-2, and decreased inhibitory binding of CDK-2 to p21Cip1. Our findings demonstrate that mevalonate promotes tumor growth and suggest that an increase in mevalonate synthesis in extrahepatic tissues following cholesterol-lowering therapy may explain the elevated risk of cancer shown in some studies.
Morphological similarity between biological structures in phylogenetically distant species is usually regarded as evidence of convergent evolution. Yet, phenotypic similarity is not always a sign of ...natural selection acting on a particular trait, therefore adaptation to similar conditions may fail to generate convergent lineages. Herein we tested whether convergent evolution occurred in the humerus of fossorial mammals, one of the most derived biological structures among mammals. Clades adapting to digging kinematics possess unusual, by mammalian standards, humeral shapes. The application of a new, computationally fast morphological test revealed a single significant instance of convergence pertaining to the Japanese fossorial moles (Mogera) and the North-American fossorial moles (Scalopini). Yet, the pattern only manifests when trade-off performance data (derived from finite element analysis) are added to shape data. This result indicates that fossorial mammals have found multiple solutions to the same adaptive challenge, independently moving around multiple adaptive peaks. This study suggests the importance of accounting for functional trade-off measures when studying morpho-functional convergence. We revealed that fossorial mammals, a classic example of convergent evolution, evolved multiple strategies to exploit the subterranean ecotope, characterized by different functional trade-offs rather than converging toward a single adaptive optimum.
Cypridoidean ostracods are one of a number of animal taxa that reproduce with giant sperm, up to 10 000 µm in length, but they are the only group to have aflagellate, filamentous giant sperm. The ...evolution and function of this highly unusual feature of reproduction with giant sperm are currently unknown. The hypothesis of long-term evolutionary persistence of this kind of reproduction has never been tested. We here report giant sperm discovered by propagation phase contrast X-ray synchrotron micro- and nanotomography, preserved in five Miocene ostracod specimens from Queensland, Australia. The specimens belong to the species Heterocypris collaris Matzke-Karasz et al. 2013 (one male and three females) and Newnhamia mckenziana Matzke-Karasz et al. 2013 (one female). The sperm are not only the oldest petrified gametes on record, but include three-dimensional subcellular preservation. We provide direct evidence that giant sperm have been a feature of this taxon for at least 16 Myr and provide an additional criterion (i.e. longevity) to test hypotheses relating to origin and function of giant sperm in the animal kingdom. We further argue that the highly resistant, most probably chitinous coats of giant ostracod sperm may play a role in delaying decay processes, favouring early mineralization of soft tissue.
The Mountain Pygmy-possum (
) is a critically endangered marsupial, endemic to alpine regions of southern Australia. We investigated the diet of a recently discovered population of the possum in ...northern Kosciuszko National Park, NSW, Australia. This new population occurs at elevations well below the once-presumed lower elevation limit of 1,600 m.
Faecal material was analysed to determine if dietary composition differed between individuals in the newly discovered northern population and those in the higher elevation southern population, and to examine how diet was influenced by rainfall in the southern population and seasonal changes in resource availability in the northern population.
The diet of
in the northern population comprised of arthropods, fruits and seeds. Results indicate the diet of both populations shares most of the same invertebrate orders and plant species. However, in the absence of preferred food types available to the southern population, individuals of the northern population opportunistically consumed different species that were similar to those preferred by individuals in higher altitude populations. Differing rainfall amounts had a significant effect on diet, with years of below average rainfall having a greater percentage composition and diversity of invertebrates. Seasonal variation was also recorded, with the northern population increasing the diversity of invertebrates in their diet during the Autumn months when Bogong Moths (
) were absent from those sites, raising questions about the possum's dependence on the species.
Measurable effects of rainfall amount and seasonal variation on the dietary composition suggest that predicted climatic variability will have a significant impact on its diet, potentially impacting its future survival. Findings suggest that it is likely that
is not restricted by dietary requirements to its current pattern of distribution. This new understanding needs to be considered when formulating future conservation strategies for this critically endangered species.
Additions of large wood (LW) have become a go-to technique for recovering altered river ecosystems. However, successful applications of this technique are generally limited to unchannelized rivers ...and headwater streams. Channelization of rivers, that is, engineering river channels to reduce recruitment and retention of in-channel structure, may, by definition, limit success of this restoration technique. Moreover, sufficient time has passed (a century or more) since initial channelization of many large rivers that portions of the fish community associated with LW may have become extirpated. Thus, the maxim that LW leads to a positive fish community response may not hold true. We examined fish community associations in habitats with and without LW in the channelized Missouri River to gain an understanding of the role of LW in large, channelized rivers. There were some differences between habitats with wood present compared to those without, but the differences were not evident once year, season and channel modifications intended to create aquatic habitat were taken into account. We assert that careful planning is necessary to ensure that additions of LW in channelized rivers are made to appropriate locations such that it will be retained in-channel for use as fish habitat and that LW-associated species are found in the system.
Melanoma differentiation associated gene-7/Interleukin-24 (MDA-7/IL-24) is a novel member of the IL-10 gene family that selectively induces apoptosis and toxic autophagy in a broad spectrum of human ...cancers, including breast cancer, without harming normal cells or tissues. The ability to investigate the critical events underlying cancer initiation and progression, as well as the capacity to test the efficacy of novel therapeutics, has been significantly advanced by the development of genetically engineered mice (GEMs) that accurately recapitulate specific human cancers. We utilized three transgenic mouse models to better comprehend the in vivo role of MDA-7/IL-24 in breast cancer. Using the MMTV-PyMT spontaneous mammary tumor model, we confirmed that exogenously introducing MDA-7/IL-24 using a Cancer Terminator Virus caused a reduction in tumor burden and also produced an antitumor "bystander" effect. Next we performed xenograft studies in a newly created MMTV-MDA-7 transgenic model that over-expresses MDA-7/IL-24 in the mammary glands during pregnancy and lactation, and found that MDA-7/IL-24 overexpression delayed tumor growth following orthotopic injection of a murine PDX tumor cell line (mPDX) derived from a tumor formed in an MMTV-PyMT mouse. We also crossed the MMTV-MDA-7 line to MMTV-Erbb2 transgenic mice and found that MDA-7/IL-24 overexpression delayed the onset of mammary tumor development in this model of spontaneous mammary tumorigenesis as well. Finally, we assessed the role of MDA-7/IL-24 in immune regulation, which can potentially contribute to tumor suppression in vivo. Our findings provide further direct in vivo evidence for the role of MDA-7/IL-24 in tumor suppression in breast cancer in immune-competent transgenic mice.
When invasive species move to new environments they typically experience population bottlenecks that limit the probability that pathogens and parasites are also moved. The invasive species may thus ...be released from biotic interactions that can be a major source of density-dependent mortality, referred to as enemy release. We examined for evidence of enemy release in populations of the common wasp (Vespula vulgaris), which attains high densities and represents a major threat to biodiversity in its invaded range. Mass spectrometry proteomic methods were used to compare the microbial communities in wasp populations in the native (Belgium and England) and invaded range (Argentina and New Zealand). We found no evidence of enemy release, as the number of microbial taxa was similar in both the introduced and native range. However, some evidence of distinctiveness in the microbial communities was observed between countries. The pathogens observed were similar to a variety of taxa observed in honey bees. These taxa included Nosema, Paenibacillus, and Yersina spp. Genomic methods confirmed a diversity of Nosema spp., Actinobacteria, and the Deformed wing and Kashmir bee viruses. We also analysed published records of bacteria, viruses, nematodes and fungi from both V. vulgaris and the related invader V. germanica. Thirty-three different microorganism taxa have been associated with wasps including Kashmir bee virus and entomophagous fungi such as Aspergillus flavus. There was no evidence that the presence or absence of these microorganisms was dependent on region of wasp samples (i.e. their native or invaded range). Given the similarity of the wasp pathogen fauna to that from honey bees, the lack of enemy release in wasp populations is probably related to spill-over or spill-back from bees and other social insects. Social insects appear to form a reservoir of generalist parasites and pathogens, which makes the management of wasp and bee disease difficult.
Statins and cancer development Duncan, Robin E; El-Sohemy, Ahmed; Archer, Michael C
Cancer epidemiology, biomarkers & prevention,
08/2005, Letnik:
14, Številka:
8
Journal Article
Recenzirano
Odprti dostop
There is epidemiologic evidence that the hydrophilic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor pravastatin increases the incidence of some extrahepatic cancers, although this ...finding has been attributed to chance. We hypothesize that pravastatin is able to promote the development of cancer by causing an induction of HMG-CoA reductase and, hence, mevalonate synthesis in extrahepatic tissues. We have shown that mevalonate, the product of HMG-CoA reductase, promotes the growth of breast cancer cells. Because there is no uptake of pravastatin by most extrahepatic cells, this statin will be unable to mitigate the increase in mevalonate synthesis in extrahepatic tissues that accompanies the decrease in circulating cholesterol caused by its inhibition of hepatic HMG-CoA reductase.
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the formation of mevalonate, a precursor of cholesterol that is also required for cell proliferation. Mevalonate depletion results ...in a G1 phase cell cycle arrest that is mediated in part by impaired activity of cyclin-dependent kinase (CDK) 2, and decreased expression of positive regulators of G1 to S phase progression. Inhibition of mevalonate synthesis may, therefore, be a useful strategy to impair the growth of malignant cells. Plant isoprenoids, including β-ionone and geraniol, have previously been shown to inhibit rodent mammary tumor development, and rodent and avian hepatic HMG-CoA reductase activity. We hypothesized that the putative anti-proliferative and cell cycle inhibitory effects of β-ionone and geraniol on MCF-7 human breast cancer cells in culture are mediated by mevalonate depletion resulting from inhibition of HMG-CoA reductase activity. Flow cytometric analysis showed a G1 arrest in isoprenoid-treated MCF-7 cells, and also a G2/M arrest at higher concentrations of isoprenoids. These compounds minimally affected the growth of MCF-10F normal breast epithelial cells. Both β-ionone and geraniol inhibited CDK 2 activity and dose-dependently decreased the expression of cyclins D1, E, and A, and CDK 2 and 4, without changing the expression of p21
cip1 or p27
kip1. Although both β-ionone and geraniol also inhibited MCF-7 proliferation, only geraniol inhibited HMG-CoA reductase activity. While these effects were significantly correlated (
r
2 = 0.89,
P < 0.01), they were not causally related, since exogenous mevalonate did not restore growth in geraniol-inhibited cells. These findings indicate that mechanisms other than impaired mevalonate synthesis mediate the anti-proliferative and cell cycle regulatory effects of β-ionone and geraniol in human breast cancer cells.
Sheath-tailed bats (Family Emballonuridae) from the early Pleistocene Rackham's Roost Site cave deposit in the Riversleigh World Heritage Area, north-western Queensland are the oldest recorded ...occurrence for the family in Australia. The fossil remains consist of maxillary and dentary fragments, as well as isolated teeth, but until now their precise identity has not been assessed. Our study indicates that at least three taxa are represented, and these are distinguished from other Australian emballonurids based on morphometric analysis of craniodental features. Most of the Rackham's Roost Site emballonurid remains are referrable to the modern species
Thomas, 1915, but the extant species
Tate, 1952 also appears to be present, as well as a very large, as-yet undetermined species of
Temminck, 1838. We identify craniodental features that clearly distinguish
from the externally very similar
. Results suggest that the distributions of
and
may have overlapped in north-western Queensland since at least the early Pleistocene.
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