Investigation of the 1758G>C and 2880A>G variants within the NCOA3 gene in a breast cancer affected Australian population

NCOA3 is a known low to moderate-risk breast cancer susceptibility gene, amplified in 5–10% and over expressed in about 60% of breast tumours. Additionally, this over expression is associated with Tamoxifen resistance and poor prognosis. Previously, two variants of NCOA3, 1758G > C and 2880A > G have been associated with breast cancer in two independent populations. Here we assessed the influence of the two NCOA3 variants on breast cancer risk by genotyping an Australian case–control study population. 172 cases and 178 controls were successfully genotyped for the 1758G > C variant and 186 cases and 182 controls were successfully genotyped for the 2880A > G variant using high-resolution melt analysis (HRM). The genotypes of the 1758G > C variant were validated by sequencing. χ2 tests were performed to determine if significant differences exist in the genotype and allele frequencies between the cases and controls. χ2 analysis returned no statistically significant difference (p > 0.05) for genotype frequencies between cases and controls for 1758G > C (χ2 = 0.97, p = 0.6158) or 2880A > G (χ2 = 2.09, p = 0.3516). Similarly, no statistical difference was observed for allele frequencies for 1758G > C (χ2 = 0.07, p = 0.7867) or 2880A > G (χ2 = 0.04, p = 0.8365). Haplotype analysis of the two SNPs also showed no difference between the cases and the controls (p = 0.9585). Our findings in an Australian Caucasian population composed of breast cancer sufferers and an age matched control population did not support the findings of previous studies demonstrating that these markers play a significant role in breast cancer susceptibility. Here, no significant difference was detected between breast cancer patients and healthy matched controls by either the genotype or allele frequencies for the investigated variants (all p ≥ 0.05). While an association of the two variants and breast cancer was not detected in our case–control study population, exploring these variants in a larger population of the same kind may obtain results in concordance with previous studies. Given the importance of NCOA3 and its involvement in biological processes involved in breast cancer and the possible implications variants of the gene could have on the response to Tamoxifen therapy, NCOA3 remains a candidate for further investigations.

G-protein β3 subunit gene (GNB3) variant in causation of essential hypertension

Essential hypertensives display enhanced signal transduction through pertussis toxin-sensitive G proteins. The T allele of a C825T variant in exon 10 of the G protein β3 subunit gene (GNB3) induces formation of a splice variant (Gβ3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 versus 0.25 in control). To confirm and extend this finding in a different setting, we performed an association study in Australian white hypertensives. This involved an extensively examined cohort of 110 hypertensives, each of whom were the offspring of 2 hypertensive parents, and 189 normotensives whose parents were both normotensive beyond age 50 years. Genotyping was performed by polymerase chain reaction and digestion with BseDI, which either cut (C allele) or did not cut (T allele) the 268-bp polymerase chain reaction product. T allele frequency in the hypertensive group was 0.43 compared with 0.25 in the normotensive group (χ2=22; P=0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolic=105±7, 109±16, and 128±28 mm Hg (mean±SD) for CC, CT, and 7T, respectively (P=0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele (P=0.006 for systolic and 0.0003 for diastolic by ANOVA) than they were in male hypertensives. In conclusion, the present study of a group with strong family history supports a role for a genetically determined, physiologically active splice variant of the G protein β3 subunit gene in the causation of essential hypertension.

Are the offences in the Copyright Act 1968 (Cth) legitimate and effective? : an analysis based in harm and social norms theory

This thesis examines the effectiveness of offences in the Copyright Act 1968 (Cth) in the online environment. The application of social norm theories suggests that the offences will be ineffective in creating an effective deterrent to non-commercial copyright infringement.

Preexercise aminoacidemia and muscle protein synthesis after resistance exercise

PURPOSE We have previously shown that the aminoacidemia caused by the consumption of a rapidly digested protein after resistance exercise enhances muscle protein synthesis (MPS) more than the amino acid (AA) profile associated with a slowly digested protein. Here, we investigated whether differential feeding patterns of a whey protein mixture commencing before exercise affect postexercise intracellular signaling and MPS. METHODS Twelve resistance-trained males performed leg resistance exercise 45 min after commencing each of three volume-matched nutrition protocols: placebo (PLAC, artificially sweetened water), BOLUS (25 g of whey protein + 5 g of leucine dissolved in artificially sweetened water; 1× 500 mL), or PULSE (15× 33-mL aliquots of BOLUS drink every 15 min). RESULTS The preexercise rise in plasma AA concentration with PULSE was attenuated compared with BOLUS (P < 0.05); this effect was reversed after exercise, with two-fold greater leucine concentrations in PULSE compared with BOLUS (P < 0.05). One-hour postexercise, phosphorylation of p70 S6K and rpS6 was increased above baseline with BOLUS and PULSE, but not PLAC (P < 0.05); furthermore, PULSE > BOLUS (P < 0.05). MPS throughout 5 h of recovery was higher with protein ingestion compared with PLAC (0.037 ± 0.007), with no differences between BOLUS or PULSE (0.085 ± 0.013 vs. 0.095 ± 0.010%•h, respectively, P = 0.56). CONCLUSIONS Manipulation of aminoacidemia before resistance exercise via different patterns of intake of protein altered plasma AA profiles and postexercise intracellular signaling. However, there was no difference in the enhancement of the muscle protein synthetic response after exercise. Protein sources producing a slow AA release, when consumed before resistance exercise in sufficient amounts, are as effective as rapidly digested proteins in promoting postexercise MPS.

Prognostic value of hTERT mRNA expression in surgical samples of lung cancer patients : the European Early Lung Cancer Project

Lung cancer is the most important cause of cancer-related mortality. Resectability and eligibility for treatment with adjuvant chemotherapy is determined by staging according to the TNM classification. Other determinants of tumour behaviour that predict disease outcome, such as molecular markers, may improve decision-making. Activation of the gene encoding human telomerase reverse transcriptase (hTERT) is implicated in the pathogenesis of lung cancer, and consequently detection of hTERT mRNA might have prognostic value for patients with early stage lung cancer. A cohort of patients who underwent a complete resection for early stage lung cancer was recruited as part of the European Early Lung Cancer (EUELC) project. In 166 patients expression of hTERT mRNA was determined in tumour tissue by quantitative real-time RT-PCR and related to that of a house-keeping gene (PBGD). Of a subgroup of 130 patients tumour-distant normal tissue was additionally available for hTERT mRNA analysis. The correlation between hTERT levels of surgical samples and disease-free survival was determined using a Fine and Gray hazard model. Although hTERT mRNA positivity in tumour tissue was significantly associated with clinical stage (Fisher's exact test p=0.016), neither hTERT mRNA detectability nor hTERT mRNA levels in tumour tissue were associated with clinical outcome. Conversely, hTERT positivity in adjacent normal samples was associated with progressive disease, 28% of patients with progressive disease versus 7.5% of disease-free patients had detectable hTERT mRNA in normal tissue [adjusted HR: 3.60 (1.64-7.94), p=0.0015]. hTERT mRNA level in tumour tissue has no prognostic value for patients with early stage lung cancer. However, detection of hTERT mRNA expression in tumour-distant normal lung tissue may indicate an increased risk of progressive disease.

Copyright exceptions beyond the Copyright Act 1968 (Cth)

Exceptions are an important part of the Australian copyright law landscape due to the role they play in delineating the extent of the rights held by copyright owners and, correspondingly, the permitted activities of users of copyright materials. The nature and scope of copyright exceptions has been examined in several reviews of copyright law and are again being considered by the Australian Law Reform Commission (ALRC) as part of the ‘Copyright and the Digital Economy’ review which is currently underway. The ALRC’s terms of reference require it to examine, inter alia, ‘whether the exceptions and statutory licences in the Copyright Act 1968, are adequate and appropriate in the digital environment.’ While the ALRC inquiry focuses on exceptions provided under the Copyright Act 1968 (Cth) (“Copyright Act”), there are several copyright exceptions in other Commonwealth statutes which are of relevance and which should not be overlooked.

Context-resonant systems perspectives in career theory

"The focus of this chapter is on context-resonant systems perspectives in career theory and their implications for practice in diverse cultural and contextual settings. For over two decades, the potential of systems theory to offer a context-resonant approach to career development has been acknowledged. Career development theory and practice, however, have been dominated for most of their history by more narrowly defined theories informed by a trait-and-factor tradition of matching the characteristics of individuals to occupations. In contrast, systems theory challenges this parts-in-isolation approach and offers a response that can accommodate the complexity of both the lives of individuals and the world of the 21st century by taking a more holistic approach that considers individuals in context. These differences in theory and practice may be attributed to the underlying philosophies that inform them. For example, the philosophy informing the trait-and-factor theoretical position, logical positivism, places value on: studying individuals in isolation from their environments; content over process; facts over feelings; objectivity over subjectivity; and views individual behavior as observable, measurable, and linear. In practice, this theory base manifests in expert-driven practices founded on the assessment of personal traits such as interests, personality, values, or beliefs which may be matched to particular occupations. The philosophy informing more recent theoretical positions, constructivism, places value on: studying individuals in their contexts; making meaning of experience through the use of subjective narrative accounts; and a belief in the capacity of individuals known as agency. In practice, this theory base manifests in practices founded on collaborative relationships with clients, narrative approaches, and a reduced emphasis on expert-driven linear processes. Thus, the tenets of constructivism which inform the systems perspectives in career theory are context-resonant. Systems theory stresses holism where the interconnectedness of all elements of a system is considered. Systems may be open or closed. Closed systems have no relationship with their external environment whereas open systems interact with their external environment and are open to external influence which is necessary for regeneration. Congruent with general systems theory, the systems perspectives emerging within career theory are based on open systems. Such systems are complex and dynamic and comprise many elements and subsystems which recursively interact with each other as well as with influences from the surrounding environment. As elements of a system should not be considered in isolation, a systems approach is holistic. Patterns of behavior are found in the relationships between the elements of dynamic systems. Because of the multiplicity of relationships within and between elements of subsystems, the possibility of linear causal explanations is reduced. Story is the mechanism through which the relationships and patterns within systems are recounted by individuals. Thus the career guidance practices emanating from theories informed by systems perspectives are inherently narrative in orientation. Narrative career counseling encourages career development to be understood from the subjective perspective of clients. The application of systemic thinking in practice takes greater account of context. In so doing, practices informed by systems theory may facilitate relevance to a diverse client group in diverse settings. In a world that has become increasingly global and diverse it seems that context-resonant systems perspectives in career theory are essential to ensure the future of career development. Translating context-resonant systems perspectives into practice offers important possibilities for methods and approaches that are respectful of diversity."--publisher website

Review : "Genetic Privacy: A challenge to Medico-Legal Norms" by Laurie, G

The discovery by Watson and Crick of the structure of DNA is one of the great scientific discoveries. In the period since that discovery new areas of genetic research have opened up which hold out the hope of developing treatments or cures for many illnesses and diseases. Yet with these discoveries have also come an array of ethical and legal dilemmas about the use of genetic information and concerns about the potential for those with genetic diseases or conditions to be stigmatised and discriminated against. The discussion about the developments in genetic science has become increasingly, a debate about the use of genetic information within our society. Graeme Laurie’s book, Genetic Privacy: A Challenge to Medico-Legal Norms, guides the reader through the complexities of these debates by considering what we mean by privacy and asking whether our existing concepts are adequate to meet the challenges posed by the new genetics.

Role of the N-terminal region in G protein-coupled receptor functions : negative modulation revealed by 5-HT2B receptor polymorphisms

The putative role of the N-terminal region of rhodopsin-like 7 transmembrane biogenic amine receptors in agonist-induced signaling has not yet been clarified despite recent advances in 7 transmembrane receptor structural biology. Given the existence of N-terminal nonsynonymous polymorphisms (R6G;E42G) within the HTR2B gene in a drug-abusing population, we assessed whether these polymorphisms affect 5-hydroxytryptamine 2B (5-HT2B) receptor in vitro pharmacologic and coupling properties in transfected COS-7 cells. Modification of the 5-HT2B receptor N terminus by the R6G;E42G polymorphisms increases such agonist signaling pathways as inositol phosphate accumulation as assessed by either classic or operational models. The N-terminal R6G;E42G mutations of the 5-HT2B receptor also increase cell proliferation and slow its desensitization kinetics compared with the wild-type receptor, further supporting a role for the N terminus in transduction efficacy. Furthermore, by coexpressing a tethered wild-type 5-HT2B receptor N terminus with a 5-HT2B receptor bearing a N-terminal deletion, we were able to restore original coupling. This reversion to normal activity of a truncated 5-HT2B receptor by coexpression of the membrane-tethered wild-type 5-HT2B receptor N terminus was not observed using a membrane-tethered 5-HT2B receptor R6G;E42G N terminus. These data suggest that the N terminus exerts a negative control over basal as well as agonist-stimulated receptor activity that is lost in the R6G;E42G mutant. Our findings reveal a new and unanticipated role of the 5-HT2B receptor N terminus as a negative modulator, affecting both constitutive and agonist-stimulated activity. Moreover, our data caution against excluding the N terminus and extracellular loops in structural studies of this 7 transmembrane receptor family

Review of penalties and additional damages : Trade Marks Act 1995

Effective enforcement of intellectual property (IP) rights has become a significant issue due to concerns about the effects of IP infringement, including trade mark counterfeiting. It is an important issue for the Australian Government as IP rights underpin a strong, modern economy. Criminal offences and civil remedies can be an important element of an enforcement regime. This review of penalties and additional damages in the Trade Marks Act 1995 (Cth) (Trade Marks Act) has been prompted by a recommendation made by the Advisory Council on Intellectual Property (ACIP), recent changes to the Copyright Act 1968 (Cth) (Copyright Act) and concerns raised by stakeholders. The purpose of this paper is to elicit comments on options which IP Australia is considering recommending to Government.

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010

BACKGROUND Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. METHODS We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. FINDINGS In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. INTERPRETATION Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.

Commentary on the article by Swanenburg et al. ‘Validity and reliability of a German version of the Neck Disability Index (NDI-G)’

We commend Swanenburg et al. (2013) on translation, development, and clinimetric analysis of the NDI-G. However, the dual-factor structure with factor analysis and the high level of internal consistency (IC) highlighted in their discussion were not emphasized in the abstract or conclusion. These points may imply some inconsistencies with the final conclusions since determination of stable point estimates with the study's small sample are exceedingly difficult.

Association of sporadic chondrocalcinosis with a -4-basepair G-to-A transition in the 5′-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate

Objective Certain mutations in ANKH, which encodes a multiple-pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal-dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis. Methods ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH-8 articular chondrocytes. Results Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5′-untranslated region (5′-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This -4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild-type ANKH and the -4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen. Conclusion A subset of sporadic chondrocalcinosis appears to be heritable via a -4-bp G-to-A ANKH 5′-UTR transition that up-regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.