Gene amplifications associated with the development of hormone- resistant prostate cancer

Purpose: Hormone resistance remains a significant clinical problem in prostate cancer with few therapeutic options. Research into mechanisms of hormone resistance is essential. Experimental Design: We analyzed 38 paired (prehormone/posthormone resistance) prostate cancer samples using the Vysis GenoSensor. Archival microdissected tumor DNA was extracted, amplified, labeled, and hybridized to Amplione I DNA microarrays containing 57 oncogenes. Results: Genetic instability increased during progression from hormone-sensitive to hormone-resistant cancer (P = 0.008). Amplification frequencies of 15 genes (TERC, MYBL3, HRAS, PI3KCA, JUNB, LAMC2, RAF1, MYC, GARP, SAS, FGFR1, PGY1, MYCL1, MYB, FGR) increased by greater than 10% during hormone escape. Receptor tyrosine kinases were amplified in 73% of cases; this was unrelated to development of hormone resistance. However, downstream receptor tyrosine kinase signaling pathways showed increased amplification rates in resistant tumors for the mitogen-activated protein kinase (FGR/Src-2, HRAS, and RAF1; P = 0.005) and phosphatidylinositol 3'-kinase pathways (FGR/ Src-2, PI3K, and Akt; P = 0.046). Transcription factors regulated by these pathways were also more frequently amplified after escape (MYC family: 21% before versus 63% after, P = 0.027; MYB family: 26 % before versus 53 % after, P = 0.18). Conclusions: Development of clinical hormone escape is linked to phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways. These pathways may function independently of the androgen receptor or via androgen receptor activation by phosphorylation, providing novel therapeutic targets

Measurement of turbulent flame speed of natural gas/air mixtures at elevated pressure

Turbulent flame speeds were measured over a range of pressures to 0.8 MPa using a jet flow apparatus fired with a synthetic mixture representing a mid-European natural gas. The equivalence ratio empty set was 0.9. The gas contained significant proportions of ballast gases and higher hydrocarbons. The method adopted was the 'flame angle' technique, using schlieren imaging to obtain the flame vertex angle from the peak density gradient. Image analysis techniques were developed to reduce interpretation errors and give an unbiased result. The data show higher flame speeds than those obtained with pure methane at elevated pressures, using similar methodology, and has an application in numerical modelling of combustors

The effects of demand characteristics on research participant behaviours in non-laboratory settings: a systematic review.

BACKGROUND: The concept of demand characteristics, which involves research participants being aware of what the researcher is investigating, is well known and widely used within psychology, particularly in laboratory-based studies. Studies of this phenomenon may make a useful contribution to broader consideration of the effects of taking part in research on participant behaviour. This systematic review seeks to summarise data from studies of the effects of demand characteristics on participant behaviours in non-laboratory settings. METHODOLOGY/PRINCIPAL FINDINGS: Electronic databases were searched to identify eligible studies. These had to be purposely designed to evaluate possible effects of demand characteristics on at least one behavioural outcome under the autonomous control of the participants and use longitudinal study designs. Only 7 studies were included, 6 providing observational data and 1 experimental study, with 5 studies involving examination of possible effects on health behaviours. Although studies provided some evidence of effects of demand characteristics on participant behaviour, heterogeneous operationalisation of the construct, the limited number of studies and poor quality of study designs made synthesis and interpretation of study findings challenging. CONCLUSIONS/SIGNIFICANCE: Although widely accepted as important in psychology, there have been few dedicated studies of the effects of demand characteristics on research participant behaviours outside laboratory settings. This body of literature does not currently contribute to the wider study of research participation effects. A systematic review of data from laboratory-based studies is needed, as are high-quality primary studies in non-laboratory settings. We suggest that unqualified use of the term demand characteristics should be abandoned

Indonesian Social Case Studies and Sociographic Data: A Longitudinal Treasure Trove

Page range: 171-172Studies and .pdfs referenced in this paper are available via the University of Sydney at this URL: https://ses.library.usyd.edu.au/handle/2123/593

Were early pterosaurs inept terrestrial locomotors?

Pterodactyloid pterosaurs are widely interpreted as terrestrially competent, erect-limbed quadrupeds, but the terrestrial capabilities of non-pterodactyloids are largely thought to have been poor. This is commonly justified by the absence of a non-pterodactyloid footprint record, suggestions that the expansive uropatagia common to early pterosaurs would restrict hindlimb motion in walking or running, and the presence of sprawling forelimbs in some species. Here, these arguments are re-visited and mostly found problematic. Restriction of limb mobility is not a problem faced by extant animals with extensive fight membranes, including species which routinely utilise terrestrial locomotion. The absence of non-pterodactyloid footprints is not necessarily tied to functional or biomechanical constraints. As with other fully terrestrial clades with poor ichnological records, biases in behaviour, preservation, sampling and interpretation likely contribute to the deficit of early pterosaur ichnites. Suggestions that non-pterodactyloids have slender, mechanically weak limbs are demonstrably countered by the proportionally long and robust limbs of many Triassic and Jurassic species. Novel assessments of pterosaur forelimb anatomies conflict with notions that all non-pterodactyloids were obligated to sprawling forelimb postures. Sprawling forelimbs seem appropriate for species with ventrally-restricted glenoid articulations (seemingly occurring in rhamphorhynchines and campylognathoidids). However, some early pterosaurs, such as Dimorphodon macronyx and wukongopterids, have glenoid arthrologies which are not ventrally restricted, and their distal humeri resemble those of pterodactyloids. It seems fully erect forelimb stances were possible in these pterosaurs, and may be probable given proposed correlation between pterodactyloid-like distal humeral morphology and forces incurred through erect forelimb postures. Further indications of terrestrial habits include antungual sesamoids, which occur in the manus and pes anatomy of many early pterosaur species, and only occur elsewhere in terrestrial reptiles, possibly developing through frequent interactions of large claws with firm substrates. It is argued that characteristics possibly associated with terrestriality are deeply nested within Pterosauria and not restricted to Pterodactyloidea as previously thought, and that pterodactyloid-like levels of terrestrial competency may have been possible in at least some early pterosaurs

Communities in action: developing a dental ambassador training programme for adults with learning disability.

Adults with learning disabilities may be at higher risk of poor oral health. The community outreach programme attached to Plymouth University Peninsula Dental School used established links with local agencies for this group to try out an intervention using service users as dental ambassadors. A programme was developed to meet the needs of the group and training in oral health key messages was provided along with support in presentation skills. Early evaluation shows promise in terms of feasibility, interest and improved self-care. Public health competencies being illustrated: Strategic leadership, communication, teaching and training, and collaborative working for health and oral health improvement

Disrupted hippocampal sharp-wave ripple-associated spike dynamics in a transgenic mouse model of dementia.

This is the peer reviewed version of the article, which has been published in final form at DOI: 10.1113/jphysiol.2014.282889. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Neurons within the CA1 region of the hippocampus are co-activated during high frequency (100-250 Hz) sharp wave ripple (SWR) activity in a manner that likely drives synaptic plasticity and promotes memory consolidation. In this study we have used a transgenic mouse model of dementia (rTg4510 mice) which overexpresses a mutant form of tau protein, to examine the effects of tauopathy on hippocampal SWRs and associated neuronal firing. Tetrodes were used to record simultaneous extracellular action potentials and local field potentials from the dorsal CA1 pyramidal cell layer of 7-8 month old wild-type and rTg4510 mice at rest in their home cage. At this age point these mice exhibit neurofibrillary tangles, neurodegeneration and cognitive deficits. Epochs of sleep or quiet restfulness were characterised by minimal locomotor activity and a low theta/delta ratio in the local field potential power spectrum. SWRs detected off-line were significantly lower in amplitude and had an altered temporal structure in rTg4510 mice. Nevertheless, the average frequency profile and duration of the SWRs were relatively unaltered. Putative interneurons displayed significantly less temporal and phase locking to SWRs in rTg4510 mice, whilst putative pyramidal neurons showed increased temporal and phase locking to SWRs. These findings indicate there is reduced inhibitory control of hippocampal network events and points to a novel mechanism which may contribute to impairments in memory consolidation in this model of dementia. This article is protected by copyright. All rights reserved.Alzheimer’s Research UKMedical Research Counci

Positive allometry and the prehistory of sexual selection

The function of the exaggerated structures that adorn many fossil vertebrates remains largely unresolved. One recurrent hypothesis is that these elaborated traits had a role in thermoregulation. This orthodoxy persists despite the observation that traits exaggerated to the point of impracticality in extant organisms are almost invariably sexually selected. We use allometric scaling to investigate the role of sexual selection and thermoregulation in the evolution of exaggerated traits of the crested pterosaur Pteranodon longiceps and the sail-backed eupelycosaurs Dimetrodon and Edaphosaurus. The extraordinarily steep positive allometry of the head crest of Pteranodon rules out all of the current hypotheses for this trait's main function other than sexual signaling. We also find interspecific patterns of allometry and sexual dimorphism in the sails of Dimetrodon and patterns of elaboration in Edaphosaurus consistent with a sexually selected function. Furthermore, small ancestral, sailbacked pelycosaurs would have been too small to need adaptations to thermoregulation. Our results question the popular view that the elaborated structures of these fossil species evolved as thermoregulatory organs and provide evidence in support of the hypothesis that Pteranodon crests and eupelycosaur sails are among the earliest and most extreme examples of elaborate sexual signals in the evolution of terrestrial vertebrates. © 2010 by The University of Chicago