Generation and characterisation of Cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature

Introduction: Inherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin. Methods: An isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age-matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX) and cellular platinum uptake (ICP-MS) was also assessed. Results: Characterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines. Conclusion: Our results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the cellular events associated with the cisplatin resistance phenotype in lung cancer. © 2013 Barr et al.

Effect of bone morphogenetic protein-4 (BMP-4) on the expression of Sox2, Oct-4 and c-Myc in human periodontal ligament cells during long-term culture

Recent studies demonstrated endogenous expression level of Sox2, Oct-4 and c-Myc is correlated with the pluripotency and successful induction of induced pluripotent stem cells (iPSCs). Periondontal ligament cells (PDLCs)have multi-lineage diferentiation capability and ability to maintain undifferentiated stage, which makes PDLCs a suitable cell source for tissue repair and regeneration. To elucidate the effect of in vitro culture condition on the stemness potential of PDLCs, we explored the cell growth, proliferation, cell cycle, and the expression of Sox2, Oct-4 and c-Myc in PDLCs from passage 1 to 7 with or without the addition of recombinant human BMP4(rhBMP4). Our results revealed that BMP-4 promoted cell growth and proliferation, arrested PDLCs in S phase of cell cycle and upregulated PI value. It was revealed that without the addition of rhBMP4, the expression of Sox2, Oct-4 and c-Myc in PDLCs only maintained nucleus location until passage 3, then lost nucleus location subsequently. The mRNA expression in PDLCs further confirmed that the level of Sox2 and Oct-4 peaked at passage 3, then decreased afterwards, whereas c-Myc maintained consistently upregulation along passages. after the treatment with rhBMP4, the expression of Sox2, Oct-4 and c-Myc in PDLCs maintained nucleus location even at passage 7 and the mRNA expression of Sox2 and Oct-4 significantly upregulated at passage 5 and 7. These results demonstrated that addition of rhBMP-4 in the culture media could improve the current culture condition for PDLCs to maintain in an undifferentiated stage.

Planning for transit system reliability using productive performance and risk assessment

Urban transit system performance may be quantified and assessed using transit capacity and productive capacity for planning, design and operational management. Bunker (4) defines important productive performance measures of an individual transit service and transit line. Transit work (p-km) captures transit task performed over distance. Transit productiveness (p-km/h) captures transit work performed over time. This paper applies productive performance with risk assessment to quantify transit system reliability. Theory is developed to monetize transit segment reliability risk on the basis of demonstration Annual Reliability Event rates by transit facility type, segment productiveness, and unit-event severity. A comparative example of peak hour performance of a transit sub-system containing bus-on-street, busway, and rail components in Brisbane, Australia demonstrates through practical application the importance of valuing reliability. Comparison reveals the highest risk segments to be long, highly productive on street bus segments followed by busway (BRT) segments and then rail segments. A transit reliability risk reduction treatment example demonstrates that benefits can be significant and should be incorporated into project evaluation in addition to those of regular travel time savings, reduced emissions and safety improvements. Reliability can be used to identify high risk components of the transit system and draw comparisons between modes both in planning and operations settings, and value improvement scenarios in a project evaluation setting. The methodology can also be applied to inform daily transit system operational management.

Planning for transit system reliability using productive performance and risk assessment

Urban transit system performance may be quantified and assessed using transit capacity and productive capacity for planning, design and operational management. Bunker (4) defines important productive performance measures of an individual transit service and transit line. Transit work (p-km) captures transit task performed over distance. Transit productiveness (p-km/h) captures transit work performed over time. This paper applies productive performance with risk assessment to quantify transit system reliability. Theory is developed to monetize transit segment reliability risk on the basis of demonstration Annual Reliability Event rates by transit facility type, segment productiveness, and unit-event severity. A comparative example of peak hour performance of a transit sub-system containing bus-on-street, busway, and rail components in Brisbane, Australia demonstrates through practical application the importance of valuing reliability. Comparison reveals the highest risk segments to be long, highly productive on street bus segments followed by busway (BRT) segments and then rail segments. A transit reliability risk reduction treatment example demonstrates that benefits can be significant and should be incorporated into project evaluation in addition to those of regular travel time savings, reduced emissions and safety improvements. Reliability can be used to identify high risk components of the transit system and draw comparisons between modes both in planning and operations settings, and value improvement scenarios in a project evaluation setting. The methodology can also be applied to inform daily transit system operational management.

A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

RcppArmadillo : accelerating R with high-performance C++ linear algebra

The R statistical environment and language has demonstrated particular strengths for interactive development of statistical algorithms, as well as data modelling and visualisation. Its current implementation has an interpreter at its core which may result in a performance penalty in comparison to directly executing user algorithms in the native machine code of the host CPU. In contrast, the C++ language has no built-in visualisation capabilities, handling of linear algebra or even basic statistical algorithms; however, user programs are converted to high-performance machine code, ahead of execution. A new method avoids possible speed penalties in R by using the Rcpp extension package in conjunction with the Armadillo C++ matrix library. In addition to the inherent performance advantages of compiled code, Armadillo provides an easy-to-use template-based meta-programming framework, allowing the automatic pooling of several linear algebra operations into one, which in turn can lead to further speedups. With the aid of Rcpp and Armadillo, conversion of linear algebra centered algorithms from R to C++ becomes straightforward. The algorithms retains the overall structure as well as readability, all while maintaining a bidirectional link with the host R environment. Empirical timing comparisons of R and C++ implementations of a Kalman filtering algorithm indicate a speedup of several orders of magnitude.

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010 : a systematic analysis for the Global Burden of Disease Study 2010

Background Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Methods Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Findings Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350 000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient −0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Interpretation Rates of YLDs per 100 000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. Funding Bill & Melinda Gates Foundation.

C-BN Single-Walled Nanotubes from Hybrid Connection of BN/C Nanoribbons: Prediction by ab initio Density Functional Calculations

We demonstrated for the first time by ab initio density functional calculation and molecular dynamics simulation that C0.5(BN)0.5 armchair single-walled nanotubes (NT) are gapless semiconductors and can be spontaneously formed via the hybrid connection of graphene/BN Nanoribbons (GNR/BNNR) at room temperature. The direct synthesis of armchair C0.5(BN)0.5 via the hybrid connection of GNR/BNNR is predicted to be both thermodynamically and dynamically stable. Such novel armchair C0.5(BN)0.5 NTs possess enhanced conductance as that observed in GNRs. Additionally, the zigzag C0.5(BN)0.5 SWNTs are narrow band gap semiconductors, which may have potential application for light emission. In light of recent experimental progress and the enhanced degree of control in the synthesis of GNRs and BNNR, our results highlight an interesting avenue for synthesizing a novel specific type of C0.5(BN)0.5 nanotube (gapless or narrow direct gap semiconductor), with potentially important applications in BNC-based nanodevices.

Australian copyright regimes and political economy of music

In this chapter I review the history of copyright in Australia through a singular and exemplary ruling of the Australian High Court made in 2012 and then relate that to the declining fortunes of Australian recorded music professionals. The case in point is Phonographic Performance Company [PPCA] of Australia Limited v Commonwealth of Australia [2012] HCA 8 (hereafter, HCA 8 2012). The case encapsulates the history of copyright law in Australia, with the judicial decision drawing substantive parts of its rationale from the Statute of Anne (8 Anne, c. 19, 1710), as well as copyright acts that regulated the Australian markets prior to 1968. More importantly the High Court decision serves to delineate some important political economic aspects of the recorded music professional in Australia and demonstrates Attali’s (1985) assertion that copyright is the mechanism through which composers are, by statute, literally excluded from capitalistic engagement as ‘productive labour’.

Support for patients with hepatitis C : An exploratory qualitative study of medical specialists’ perceptions

Objective: To explore the range of meanings about the role of support for patients with hepatitis C by examining medical specialists' perceptions. Method: The study employed a qualitative, open-ended interview design and was conducted in four major teaching hospitals in Adelaide, South Australia. Eight participants (three infectious disease physicians, four gastroenterologists, one hepatologist), selected through purposive sampling, were interviewed about general patient support, their role in support provision, the role of non-medical support and their reasons for not using support services. Results: Main themes included a focus on support as information provision and that patient education is best carried out by a medical specialist. The use of support services was defined as the patient's decision. Participants identified four key periods when patients would benefit from support; during diagnosis, failure to meet treatment criteria, during interferon treatment and following treatment failure. Conclusions: It was concluded that while barriers exist to the establishment of partnerships between specialists and other support services, this study has identified clear points at which future partnerships could be established. Implications: A partnership approach to developing support for patients with hepatitis C offers a systematic framework to facilitate the participation of health professionals and the community in an important area of public health.

A revision of Calyptochloa C.E.Hubb. (Poaceae), with two new species and a new subspecies

Thompson, E.J. & Simon, B.K. (2012). A revision of Calyptochloa C.E.Hubb. (Poaceae), with two new species and a new subspecies. Austrobaileya 8(4): 634–652. Two new species of Calyptochloa C.E.Hubb. (Calyptochloa cylindrosperma E.J.Thomps. & B.K.Simon and C. johnsoniana E.J.Thomps. & B.K.Simon) endemic to central Queensland, and a new subspecies of Calyptochloa gracillima C.E.Hubb. (C. gracillima subsp. ipsviciensis E.J.Thomps. & B.K.Simon) endemic to southeast Queensland are described and illustrated.

Vitamin C : effects of exercise and requirements with training

Ascorbic acid or vitamin C is involved in a number of biochemical pathways that are important to exercise metabolism and the health of exercising individuals. This review reports the results of studies investigating the requirement for vitamin C with exercise on the basis of dietary vitamin C intakes, the response to supplementation and alterations in plasma, serum, and leukocyte ascorbic acid concentration following both acute exercise and regular training. The possible physiological significance of changes in ascorbic acid with exercise is also addressed. Exercise generally causes a transient increase in circulating ascorbic acid in the hours following exercise, but a decline below pre-exercise levels occurs in the days after prolonged exercise. These changes could be associated with increased exercise-induced oxidative stress. On the basis of alterations in the concentration of ascorbic acid within the blood, it remains unclear if regular exercise increases the metabolism of vitamin C. However, the similar dietary intakes and responses to supplementation between athletes and nonathletes suggest that regular exercise does not increase the requirement for vitamin C in athletes. Two novel hypotheses are put forward to explain recent findings of attenuated levels of cortisol postexercise following supplementation with high doses of vitamin C.

Hepatitis C in the workplace : a survey of women’s occupational health and safety in the beauty therapy industry

Objective: To examine current knowledge and practice of occupational health and safety (OH&S) regarding hepatitis C in beauty therapy practice. Methods: A questionnaire was sent to all beauty therapy practices identified through the Telstra Yellow Pages and distributed via beauty therapy product agencies. Results: 119 questionnaires were completed by employers and employees in 99 beauty therapy practices in metropolitan Adelaide. Beauty therapists reported carrying out many practices that had exposed them to blood in the past. More than 80% of the procedures carried out by beauty therapists in the previous week were reported to have led to exposure to blood. 39.5% of respondents had not received information about OH&S practices related to blood spills and 77.5% of respondents had received no OH&S information about hepatitis C. Knowledge of hepatitis C and its transmission was poor, with 62% of respondents incorrectly identifying the prevalence of hepatitis C and respondents incorrectly identifying sneezing (28%), kissing (46%) and sharing coffee cups (42%) as a modes of transmission. 80% of beauty therapy practices had no OH&S representative. Conclusion: Beauty therapy practice can expose both operator and client to blood and is therefore a potential site for the transmission of blood-borne diseases including hepatitis C. OH&S information is inadequate in this industry and knowledge of hepatitis C is poor.

Integrated genomic characterization of endometrial carcinoma

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Hepatitis C : a socio-cultural perspective on the effects of a new virus on a community’s health

Since the emergence of diagnostic medical tests in Australia in 1990, hepatitis C (HCV) has been shown to account for over 90 percent of all non-A non-B hepatitis, revealing it to be a widespread and major public health problem. The diagnosis of HCV involves a diverse range of issues for affected persons, introducing identity and lifestyle changes, which are commonly articulated through psychological concepts. In this article we argue that it is important to examine the broader social and cultural contexts that contribute to the experiences of persons affected by HCV. The thematic analysis of qualitative data from six individuals diagnosed with HCV is included to exemplify some of the processes that are involved in the changing identity of a person following a positive diagnosis. The theoretical framework for the interpretation of these processes is interpretive interactionism. In this research, we are attempting to extend the understanding of the effects of HCV diagnoses beyond internal, psychological processes by examining how these diagnoses transform some of the processes of self-formation and expression. The participants’ experiences indicate that there are at least four dimensions of self that were significant to their changing sense of self: relationship of self to others; the emotional self; self-stories and identity; and self-scrutiny and relationships. We conclude that a socio-cultural perspective contributes to the explanation of the transition period following a HCV-positive diagnosis and the redefinition of self towards a HCV status.