Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript

Abstract Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10−22). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10−34). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.

Insulin increases De Novo Steroidogenesis in prostate cancer cells

Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis.

Mitochondrial genome deletions and minicircles are common in lice (Insecta: Phthiraptera)

Background The gene composition, gene order and structure of the mitochondrial genome are remarkably stable across bilaterian animals. Lice (Insecta: Phthiraptera) are a major exception to this genomic stability in that the canonical single chromosome with 37 genes found in almost all other bilaterians has been lost in multiple lineages in favour of multiple, minicircular chromosomes with less than 37 genes on each chromosome. Results Minicircular mt genomes are found in six of the ten louse species examined to date and three types of minicircles were identified: heteroplasmic minicircles which coexist with full sized mt genomes (type 1); multigene chromosomes with short, simple control regions, we infer that the genome consists of several such chromosomes (type 2); and multiple, single to three gene chromosomes with large, complex control regions (type 3). Mapping minicircle types onto a phylogenetic tree of lice fails to show a pattern of their occurrence consistent with an evolutionary series of minicircle types. Analysis of the nuclear-encoded, mitochondrially-targetted genes inferred from the body louse, Pediculus, suggests that the loss of mitochondrial single-stranded binding protein (mtSSB) may be responsible for the presence of minicircles in at least species with the most derived type 3 minicircles (Pediculus, Damalinia). Conclusions Minicircular mt genomes are common in lice and appear to have arisen multiple times within the group. Life history adaptive explanations which attribute minicircular mt genomes in lice to the adoption of blood-feeding in the Anoplura are not supported by this expanded data set as minicircles are found in multiple non-blood feeding louse groups but are not found in the blood-feeding genus Heterodoxus. In contrast, a mechanist explanation based on the loss of mtSSB suggests that minicircles may be selectively favoured due to the incapacity of the mt replisome to synthesize long replicative products without mtSSB and thus the loss of this gene lead to the formation of minicircles in lice.

Towards robust night and day place recognition using visible and thermal imaging

The chief challenge facing persistent robotic navigation using vision sensors is the recognition of previously visited locations under different lighting and illumination conditions. The majority of successful approaches to outdoor robot navigation use active sensors such as LIDAR, but the associated weight and power draw of these systems makes them unsuitable for widespread deployment on mobile robots. In this paper we investigate methods to combine representations for visible and long-wave infrared (LWIR) thermal images with time information to combat the time-of-day-based limitations of each sensing modality. We calculate appearance-based match likelihoods using the state-of-the-art FAB-MAP [1] algorithm to analyse loop closure detection reliability across different times of day. We present preliminary results on a dataset of 10 successive traverses of a combined urban-parkland environment, recorded in 2-hour intervals from before dawn to after dusk. Improved location recognition throughout an entire day is demonstrated using the combined system compared with methods which use visible or thermal sensing alone.

Monocular amblyopia and higher order aberrations

This study compared the corneal and total higher order aberrations between the fellow eyes in monocular amblyopia. Nineteen amblyopic subjects (8 refractive and 11 strabismic) (mean age 30 ± 11 years) were recruited. A range of biometric and optical measurements were collected from the amblyopic and non-amblyopic eye including; axial length, corneal topography and total higher order aberrations. For a sub-group of eleven non-presbyopic subjects (6 refractive and 5 strabismic amblyopes, mean age 29 ± 10 years) total higher order aberrations were also measured during accommodation (2.5 D stimuli). Amblyopic eyes were significantly shorter and more hyperopic compared to non-amblyopic eyes and the interocular difference in axial length correlated with both the magnitude of anisometropia and amblyopia (both p < 0.01). Significant differences in higher order aberrations were observed between fellow eyes, which varied with the type of amblyopia. Refractive amblyopes displayed higher levels of 4th order corneal aberrations C(4, 0)(spherical aberration), C(4, 2)(secondary astigmatism 90°) and C(4, −2)(secondary astigmatism along 45°) in the amblyopic eye compared to the non-amblyopic eye. Strabismic amblyopes exhibited significantly higher levels of C(3, 3)(trefoil) in the amblyopic eye for both corneal and total higher order aberrations. During accommodation, the amblyopic eye displayed a significantly greater lag of accommodation compared to the non-amblyopic eye, while the changes in higher order aberrations were similar in magnitude between fellow eyes. Asymmetric visual experience during development appears to be associated with asymmetries in higher order aberrations, in some cases proportional to the magnitude of anisometropia and dependent upon the amblyogenic factor.

Negative change and job outcomes : the impact of subjective fit in public sector health care organization

There is an ongoing level of organizational-wide change (such as empowerment and downsizing) occurring within the Australian health care sector. However, there is a paucity of empirical evidence on how public and nonprofit sector nurses cope with these organizational-wide change initiatives and their consequences on individual and work outcomes. This will be the primary aim of the current paper. To this end, a path model is developed base on an integration of existing theoretical perspectives on occupational stress, change management, and person-organizational fit. Data were collected from 252 public and not-for-profit sector nurses. The path analysis suggests that public and nonprofit nurses experience positive and negative change initiatives. Negative change initiatives resulted in an increase in the level of administrative-related stressors. Nurses with more congruent values report less experience with administrative stressors. As nurses experienced more administrative stressors, they tend to report more job dissatisfaction. Nurses whose values were more congruent during organizational change reported higher level of psychological wellbeing. Nurses who were had higher level of psychological wellbeing were found to have higher job satisfaction, which subsequently led to a higher level of organizational commitment.