Targeting amino acid transport in metastatic castration-resistant prostate cancer : effects on cell cycle, cell growth, and tumor development

Background L-type amino acid transporters (LATs) uptake neutral amino acids including L-leucine into cells, stimulating mammalian target of rapamycin complex 1 signaling and protein synthesis. LAT1 and LAT3 are overexpressed at different stages of prostate cancer, and they are responsible for increasing nutrients and stimulating cell growth. Methods We examined LAT3 protein expression in human prostate cancer tissue microarrays. LAT function was inhibited using a leucine analog (BCH) in androgen-dependent and -independent environments, with gene expression analyzed by microarray. A PC-3 xenograft mouse model was used to study the effects of inhibiting LAT1 and LAT3 expression. Results were analyzed with the Mann-Whitney U or Fisher exact tests. All statistical tests were two-sided. Results LAT3 protein was expressed at all stages of prostate cancer, with a statistically significant decrease in expression after 4–7 months of neoadjuvant hormone therapy (4–7 month mean = 1.571; 95% confidence interval = 1.155 to 1.987 vs 0 month = 2.098; 95% confidence interval = 1.962 to 2.235; P = .0187). Inhibition of LAT function led to activating transcription factor 4–mediated upregulation of amino acid transporters including ASCT1, ASCT2, and 4F2hc, all of which were also regulated via the androgen receptor. LAT inhibition suppressed M-phase cell cycle genes regulated by E2F family transcription factors including critical castration-resistant prostate cancer regulatory genes UBE2C, CDC20, and CDK1. In silico analysis of BCH-downregulated genes showed that 90.9% are statistically significantly upregulated in metastatic castration-resistant prostate cancer. Finally, LAT1 or LAT3 knockdown in xenografts inhibited tumor growth, cell cycle progression, and spontaneous metastasis in vivo. Conclusion Inhibition of LAT transporters may provide a novel therapeutic target in metastatic castration-resistant prostate cancer, via suppression of mammalian target of rapamycin complex 1 activity and M-phase cell cycle genes.

Built heritage management systems : the framework of a digital tool for the conservation of Brisbane City Hall

Brisbane City Hall (BCH) is arguably one of Brisbane’s most notable and iconic buildings. Serving as the public’s central civic and municipal building since 1930, the importance of this heritage listed building to cultural significance and identity is unquestionable. This attribute is reflected within the local government, with a simplified image of the halls main portico entrance supplying Brisbane City Council with its insignia and trademark signifier. Regardless of these qualities, this building has been neglected in a number of ways, primarily in the physical sense with built materials, but also, and just as importantly, through inaccurate and undocumented works. Numerous restoration and renovation works have been undertaken throughout BCH’s lifetime, however the records of these amendments are far and few between. Between 2010 and 2013, BCH underwent major restoration works, the largest production project undertaken on the building since its initial construction. Just prior to this conservation process, the full extent of the buildings deterioration was identified, much of which there was little to no original documentation of. This has led to a number of issues pertaining to what investigators expected to find within the building, versus what was uncovered (the unexpected), which have resulted directly from this lack of data. This absence of record keeping is the key factor that has contributed to the decay and unknown deficiencies that had amassed within BCH. Accordingly, this raises a debate about the methods of record keeping, and the need for a more advanced process that is able to be integrated within architectural and engineering programs, whilst still maintaining the ability to act as a standalone database. The immediate objective of this research is to investigate the restoration process of BCH, with focus on the auditorium, to evaluate possible strategies to record and manage data connected to building pathology so that a framework can be developed for a digital heritage management system. The framework produced for this digital tool will enable dynamic uses of a centralised database and aims to reduce the significant data loss. Following an in-depth analysis of this framework, it can be concluded that the implementation of the suggested digital tool would directly benefit BCH, and could ultimately be incorporated into a number of heritage related built form.