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Background: Current diagnostic tools are unable to distinguish low‐grade indolent prostate cancer (PrCa) from that with a propensity to become metastatic and/or lethal. Recent evidence suggests that reprogramming of the transcriptome may drive the metastatic phenotype, and that this reprogramming is controlled, at least in part, by epigenetic changes to the DNA of cancer cells, including methylation. These changes, referred to as 'epigenetic drivers,' have previously been associated with cancer cell survival. Methods: Here, using Illumina Methylation EPIC array data of paired primary PrCa and metastatic bone samples, we identified WNT5A as a putative epi‐driver of PrCa metastasis to the bone, which was further validated in vitro. Results: Significantly higher WNT5A methylation was observed in primary PrCa samples and 22Rv1 cells compared to metastatic bone samples and PC‐3 cells. This higher methylation was associated with significantly lower WNT5A gene expression. Conclusion: Given the limited effective therapies available for metastatic cancer sufferers, particularly those whose disease has metastasised to the bone, WNT5A presents as a potential putative target for therapy. [ABSTRACT FROM AUTHOR]

Prostate cancer (PrCa) is highly heritable, and although rare variants contribute significantly to PrCa risk, few have been identified to date. Herein, whole‐genome sequencing was performed in a large PrCa family featuring multiple affected relatives spanning several generations. A rare, predicted splice site EZH2 variant, rs78589034 (G > A), was identified as segregating with disease in all but two individuals in the family, one of whom was affected with lymphoma and bowel cancer and a female relative. This variant was significantly associated with disease risk in combined familial and sporadic PrCa datasets (n = 1551; odds ratio [OR] = 3.55, P = 1.20 × 10−5). Transcriptome analysis was performed on prostate tumour needle biopsies available for two rare variant carriers and two wild‐type cases. Although no allele‐dependent differences were detected in EZH2 transcripts, a distinct differential gene expression signature was observed when comparing prostate tissue from the rare variant carriers with the wild‐type samples. The gene expression signature comprised known downstream targets of EZH2 and included the top‐ranked genes, DUSP1, FOS, JUNB and EGR1, which were subsequently validated by qPCR. These data provide evidence that rs78589034 is associated with increased PrCa risk in Tasmanian men and further, that this variant may be associated with perturbed EZH2 function in prostate tissue. Disrupted EZH2 function is a driver of tumourigenesis in several cancers, including prostate, and is of significant interest as a therapeutic target. What's new? Prostate cancer has high heritability, yet few risk variants have been identified. Here, the authors went looking for rare variants using whole genome sequencing (WGS). They tested three members of a large, multigenerational Tasmanian family with a high proportion of prostate cancer cases. WGS turned up a rare variant in EZH2, a gene that has previously been associated with prostate tumorigenesis. The researchers found the variant was associated with PrCa both in familial and sporadic cases. Tumor analysis suggests that the mutation disrupts EZH2 function and alters the expression of downstream targets. [ABSTRACT FROM AUTHOR]

Introduction: Various pressures exist for curricular change, including economic forces, burgeoning knowledge, broadening learning outcomes, and improving quality and outcomes of learning experiences. In an Australian 5-year undergraduate medical course, staff were asked to reduce teaching hours by 20% to alleviate perceived overcrowded preclinical curriculum, achieve operating efficiencies and liberate time for students' self-directed learning. Methods: A case study design with mixed methods was used to evaluate outcomes. Results: Teaching hours were reduced by 198 hours (14%) overall, lectures by 153 hours (19%) and other learning activities by 45 hours (7%). Summative assessment scores did not change significantly after the reductions: 0.4% increase, 1.5% decrease and 1.7% increase in Years 1, 2 and 3, respectively. The percentage of students successfully completing their academic year did not change significantly: 94.4% before and 93.3% after the reductions. Student evaluations from eVALUate surveys changed little, except workload was perceived to be more reasonable. Conclusions: Teaching hours, particularly lectures, can be moderately reduced with little impact on student learning outcomes or satisfaction with an undergraduate medical course. [ABSTRACT FROM AUTHOR]

The neonatal immune environment and the events that occur during this time have profound effects for the adult period. While protective immune responses can develop, the neonatal immune system, particularly the skin immune system (SIS), tends to promote tolerance. With this information we undertook a number of studies to identify unique aspects of skin during the neonatal period. Proteomics revealed proteins uniquely expressed in neonatal, but not adult, skin ( e.g. Stefin A, peroxiredoxins) and these may have implications in the development of SIS. Vitamin D was found to have a modulating role on SIS and this was apparent from the early neonatal period. Exposure of the neonatal skin to UV radiation altered the microenvironment resulting in the generation of regulatory T cells, which persisted in adult life. As the development of UV radiation-induced melanoma can occur following a single high dose (equivalent to burning in adults) to transgenic mice (hepatocyte growth factor/scatter factor or TPras) during the neonatal period, the early modulating events which lead to suppression may be relevant for the development of UV radiation-induced human melanoma. Any attempt to produce effective melanoma immunotherapy has to accommodate and overcome these barriers. Margaret Kripke’s pioneering work on UV-induced immunosuppression still remains central to the understanding of the development of melanoma and how it frequently escapes the immune system. [ABSTRACT FROM AUTHOR]

The Skin Immune System (SIS) is a relatively new concept central to the issue of cutaneous tumour surveillance. The Langerhans cell (LC) is a key component of SIS. Skin cancer causing agents such as ultraviolet B (UV-B) irradiation and chemical carcinogens like dimethylbenz(a)anthracene (DMBA) alter LC function, resulting in immunosuppression and the promotional phase of tumour development. Once tumours, such as melanoma, are established they may show evidence of tumour regression due to immune reaction but frequently escape immune attack and metastasise. This article explores our knowledge of LC and SIS in these responses. For tumour immunosurveillance to be an effective reality at the clinical level, experiments are required to provide a more precise base for immunotherapy.