'Big data' approaches for novel anti-cancer drug discovery

Introduction: The development of improved cancer therapies is frequently cited as an urgent unmet medical need. Here we review how recent advances in platform technologies and the increasing availability of biological ‘big data’ are providing an unparalleled opportunity to systematically identify the key genes and pathways involved in tumorigenesis. We then discuss how these discoveries may be amenable to therapeutic interventions. Areas covered: We discuss the current approaches that use ‘big data’ to identify cancer drivers. These approaches include genomic sequencing, pathway data, multi-platform data, identifying genetic interactions such as synthetic lethality and using cell line data. We review how big data is being used to assess the tractability of potential drug targets and how systems biology is being utilised to identify novel drug targets. We finish the review with an overview of available data repositories and tools being used at the forefront of cancer drug discovery. Expert opinion: Targeted therapies based on the genomic events driving the tumour will eventually inform treatment protocols. However, using a tailored approach to treat all tumour patients may require developing a large repertoire of targeted drugs

Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2

The Ras oncogene products regulate the expression of genes in transformed cells, and members of the Ets family of transcription factors have been implicated in this process. To determine which Ets factors are the targets of Ras signaling pathways, the abilities of several Ets factors to activate Ras-responsive enhancer (RRE) reporters in the presence of oncogenic Ras were examined. In transient transfection assay, reporters containing RREs composed of Ets-AP-1 binding sites could be activated 30-fold in NIH 3T3 fibroblasts and 80-fold in the macrophage-like line RAW264 by the combination of Ets1 or Ets2 and Ras but not by several other Ets factors that were tested in the assay. Ets2 and Ras also superactivated an RRE composed of Ets-Ets binding sites, but the Ets-responsive promoter of the c-fms gene was not superactivated. Mutation of a threonine residue to alanine in the conserved amino-terminal regions of Ets1 and Ets2 (threonine 38 and threonine 72, respectively) abrogated the ability of each of these proteins to superactivate reporter gene expression. Phosphoamino acid analysis of radiolabeled Ets2 revealed that Ras induced normally absent threonine-specific phosphorylation of the protein. The Ras-dependent increase in threonine phosphorylation was not observed in Ets2 proteins that had the conserved threonine 72 residue mutated to alanine or serine. These data indicate that Ets1 and Ets2 are specific nuclear targets of Ras signaling events and that phosphorylation of a conserved threonine residue is a necessary molecular component of Ras-mediated activation of these transcription factors

Exploring efficacy in personal constraint negotiation: an ethnography of mountaineering tourists

Limited work has explored the relationship between efficacy and personal constraint negotiation for adventure tourists, yet efficacy is pivotal to successful activity participation as it influences people’s perceived ability to cope with constraints, and their decision to use negotiation strategies. This paper explores these themes with participants of a commercially organised mountaineering expedition. Phenomenology-based ethnography was adopted to appreciate the social and cultural mountaineering setting from an emic perspective. Ethnography is already being used to understand adventure participation, yet there is considerable scope to employ it further through researchers immersing themselves into the experience. The findings capture the interaction between the ethnographer and the group members, and provide an embodied account using their lived experiences. Findings reveal that personal mountaineering skills, personal fitness, altitude sickness and fatigue were the four key types of personal constraint. Self-efficacy, negotiation-efficacy and other factors, such as hardiness and motivation, influenced the effectiveness of negotiation strategies. Training, rest days, personal health, and positive self-talk were negotiation strategies. A conceptual model illustrates these results and demonstrates the interplay between efficacy and the personal constraint negotiation journey for led mountaineers

Selective deletion of cochlear hair cells causes rapid age-dependent changes in spiral ganglion and cochlear nucleus neurons

During nervous system development, critical periods are usually defined as early periods during which manipulations dramatically change neuronal structure or function, whereas the same manipulations in mature animals have little or no effect on the same property. Neurons in the ventral cochlear nucleus (CN) are dependent on excitatory afferent input for survival during a critical period of development. Cochlear removal in young mammals and birds results in rapid death of target neurons in the CN. Cochlear removal in older animals results in little or no neuron death. However, the extent to which hair-cell-specific afferent activity prevents neuronal death in the neonatal brain is unknown. We further explore this phenomenon using a new mouse model that allows temporal control of cochlear hair cell deletion. Hair cells express the human diphtheria toxin (DT) receptor behind the Pou4f3 promoter. Injections of DT resulted in nearly complete loss of organ of Corti hair cells within 1 week of injection regardless of the age of injection. Injection of DT did not influence surrounding supporting cells directly in the sensory epithelium or spiral ganglion neurons (SGNs). Loss of hair cells in neonates resulted in rapid and profound neuronal loss in the ventral CN, but not when hair cells were eliminated at a more mature age. In addition, normal survival of SGNs was dependent on hair cell integrity early in development and less so in mature animals. This defines a previously undocumented critical period for SGN survival

A Preliminary Study of the Role of Gastrointestinal Endocrine Cells in the Maintenance of Villous Structure Following X-Irradiation

The mechanism of gastrointestinal villous damage following ionizing irradiation is complex. Various compartments within the gastrointestinal tract have in turn been considered important for the maintenance of normal villous structure. To date, however, evidence for a single overriding regulator of epithelial well-being is lacking. In this study, the role of the gastrointestinal (enteroendocrine) cells is explored and comparison made between endocrine cell number and villous structure. Experiments were organised using hath control and irradiated groups of mice. Two time points (1 and 3 days) and three radiation doses (6, 10 and 18Gy) were employed. A simple method for endocrine cell identification and subsequent quantification is described. Endocrine cell number was then compared with villous surface detail, as seen with a scanning electron microscope (SEM). Results indicated a decrease in the endocrine cell number at all three radiation doses. Whereas at low doses endocrine cell recovery occurred between 1 and 3 days, at medium and high doses further decline was noticed. A similar pattern was seen when considering villous surface structure. It is suggested that both scanning electron microscopy and endocrine cell number provide a more sensitive indicator of gastrointestinal radiation damage than do current crypt counting techniques. In addition, a link between endocrine cell number and villous structure is proposed

Early Effects on the Morphology of Mouse Small Intestine of Single or Combined Modality Treatment with Hyperthermia and X-Irradiation

This study describes the effects of hyperthermia and X-irradiation on the morphological appearance of normal, at risk tissues in the ileum of the mouse. The early morphological effects day after a combined modality treatment are compared with those due to either hyperthermia or X-irradiation given alone. The response was assessed qualitatively and semiquantitatively using scanning electron microscopy and a villous scoring technique. Early post-irradiation effects on topography did not differ significantly from those observed after small intestine exteriorisation without treatment. The villous scores for the combined modality treatments reflected greater damage than would be expected from the sum of villous scores for each modality treatment on its own. This suggests that the combined modality treatment had a synergistic or enhancing effect. A 4 hour time interval between the two treatments did not seem to reduce the enhancing effect. Further studies are required to investigate the effects of fractionated combined treatment