PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11–19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.

The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women

Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms, FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype [odds ratio (OR) = 1.17; 95% confidence interval (CI): 1.03–1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91–1.06; p = 0.68). FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.

Communications materials on methods of development of revenue and cost estimates to non-technical audiences

This CDROM includes PDFs of presentations on the following topics: "TXDOT Revenue and Expenditure Trends;" "Examine Highway Fund Diversions, & Benchmark Texas Vehicle Registration Fees;" "Evaluation of the JACK Model;" "Future highway construction cost trends;" "Fuel Efficiency Trends and Revenue Impact"

Safety leaders’ perceptions of safety culture in a large Australasian construction organisation

This paper reports safety leaders’ perceptions of safety culture in one of Australasia’s largest construction organisations. A modified Delphi method was used including two rounds of data collection. The first round involved 41 semi-structured interviews with safety leaders within the organisation. The second round involved an online quantitative perception survey, with the same sample, aimed at confirming the key themes identified in the interviews. Participants included Senior Executives, Corporate Managers, Project Managers, Safety Managers and Site Supervisors. Interview data was analysed using qualitative thematic analysis, and the survey data was analysed using descriptive statistics. Leaders’ definitions and descriptions of safety culture were primarily action-oriented and some confusion was evident due to the sometimes implicit nature of culture in organisations. Leadership was identified as a key factor for positive safety culture in the organisation, and there was an emphasis on leaders demonstrating commitment to safety, and being visible to the project-based workforce. Barriers to safety culture improvement were also identified, including the subcontractor management issues, pace of change, and reporting requirements. The survey data provided a quantitative confirmation of the interview themes, with some minor discrepancies. The findings highlight that safety culture is a complex construct, which is difficult to define, even for experts in the organisation. Findings on the key factors indicated consistency with the current literature; however the perceptions of barriers to safety culture offer a new understanding in to how safety culture operates in practice.

Thermal performance of non-load bearing LSF walls using numerical studies

Fire safety of light gauge cold-formed steel frame (LSF) wall systems is significant to the build-ing design. Gypsum plasterboard is widely used as a fire safety material in the building industry. It contains gypsum (CaSO4.2H2O), Calcium Carbonate (CaCO3) and most importantly free and chemically bound water in its crystal structure. The dehydration of the gypsum and the decomposition of Calcium Carbonate absorb heat, which gives the gypsum plasterboard fire resistant qualities. Recently a new composite panel system was developed, where a thin insulation layer was used externally between two plasterboards to improve the fire performance of LSF walls. In this research, finite element thermal models of both the traditional LSF wall panels with cavity insulation and the new LSF composite wall panels were developed to simulate their thermal behaviour under standard and realistic design fire conditions. Suitable thermal properties of gypsum plaster-board, insulation materials and steel were used. The developed models were then validated by comparing their results with fire test results. This paper presents the details of the developed finite element models of non-load bearing LSF wall panels and the thermal analysis results. It has shown that finite element models can be used to simulate the thermal behaviour of LSF walls with varying configurations of insulations and plasterboards. The results show that the use of cavity insulation was detrimental to the fire rating of LSF walls while the use of external insulation offered superior thermal protection. Effects of real fire conditions are also presented.

Near infrared spectroscopy for non-destructive evaluation of articular cartilage

There is a need for an accurate real-time quantitative system that would enhance decision-making in the treatment of osteoarthritis. To achieve this objective, significant research is required that will enable articular cartilage properties to be measured and categorized for health and functionality without the need for laboratory tests involving biopsies for pathological evaluation. Such a system would provide the capability of access to the internal condition of the cartilage matrix and thus extend the vision-based arthroscopy that is currently used beyond the subjective evaluation of surgeons. The system required must be able to non-destructively probe the entire thickness of the cartilage and its immediate subchondral bone layer. In this thesis, near infrared spectroscopy is investigated for the purpose mentioned above. The aim is to relate it to the structure and load bearing properties of the cartilage matrix to the near infrared absorption spectrum and establish functional relationships that will provide objective, quantitative and repeatable categorization of cartilage condition outside the area of visible degradation in a joint. Based on results from traditional mechanical testing, their innovative interpretation and relationship with spectroscopic data, new parameters were developed. These were then evaluated for their consistency in discriminating between healthy viable and degraded cartilage. The mechanical and physico-chemical properties were related to specific regions of the near infrared absorption spectrum that were identified as part of the research conducted for this thesis. The relationships between the tissue's near infrared spectral response and the new parameters were modeled using multivariate statistical techniques based on partial least squares regression (PLSR). With significantly high levels of statistical correlation, the modeled relationships were demonstrated to possess considerable potential in predicting the properties of unknown tissue samples in a quick and non-destructive manner. In order to adapt near infrared spectroscopy for clinical applications, a balance between probe diameter and the number of active transmit-receive optic fibres must be optimized. This was achieved in the course of this research, resulting in an optimal probe configuration that could be adapted for joint tissue evaluation. Furthermore, as a proof-of-concept, a protocol for obtaining the new parameters from the near infrared absorption spectra of cartilage was developed and implemented in a graphical user interface (GUI)-based software, and used to assess cartilage-on-bone samples in vitro. This conceptual implementation has been demonstrated, in part by the individual parametric relationship with the near infrared absorption spectrum, the capacity of the proposed system to facilitate real-time, non-destructive evaluation of cartilage matrix integrity. In summary, the potential of the optical near infrared spectroscopy for evaluating articular cartilage and bone laminate has been demonstrated in this thesis. The approach could have a spin-off for other soft tissues and organs of the body. It builds on the earlier work of the group at QUT, enhancing the near infrared component of the ongoing research on developing a tool for cartilage evaluation that goes beyond visual and subjective methods.

Experimental studies of non-load bearing steel wall systems under fire conditions

Fire safety of buildings has been recognised as very important by the building industry and the community at large. Traditionally, increased fire rating is provided by simply adding more plasterboards to light gauge steel frame (LSF) walls, which is inefficient. Many research studies have been undertaken to investigate the thermal behaviour of traditional LSF stud wall systems under standard fire conditions. However, no research has been undertaken on the thermal behaviour of LSF stud walls using the recently proposed composite panel. Extensive fire testing of both non-load bearing and load bearing wall panels was conducted in this research based on the standard time-temperature curve in AS1530.4. Three groups of LSF wall specimens were tested with no insulation, cavity insulation and the new composite panel based on an external insulation layer between plasterboards. This paper presents the details of this experimental study into the thermal performance of non-load bearing walls lined with various configurations of plasterboard and insulation. Extensive descriptive and numerical results of the tested non-load bearing wall panels given in this paper provide a thorough understanding of their thermal behaviour, and valuable time-temperature data that can be used to validate numerical models. Test results showed that the innovative composite stud wall systems outperformed the traditional stud wall systems in terms of their thermal performance, giving a much higher fire rating.