SNP technologies for drug discovery : a current review

Single nucleotide polymorphisms (SNPs) are unique genetic differences between individuals that contribute in significant ways to the determination of human variation including physical characteristics like height and appearance as well as less obvious traits such as personality, behaviour and disease susceptibility. SNPs can also significantly influence responses to pharmacotherapy and whether drugs will produce adverse reactions. The development of new drugs can be made far cheaper and more rapid by selecting participants in drug trials based on their genetically determined response to drugs. Technology that can rapidly and inexpensively genotype thousands of samples for thousands of SNPs at a time is therefore in high demand. With the completion of the human genome project, about 12 million true SNPs have been identified to date. However, most have not yet been associated with disease susceptibility or drug response. Testing for the appropriate drug response SNPs in a patient requiring treatment would enable individualised therapy with the right drug and dose administered correctly the first time. Many pharmaceutical companies are also interested in identifying SNPs associated with polygenic traits so novel therapeutic targets can be discovered. This review focuses on technologies that can be used for genotyping known SNPs as well as for the discovery of novel SNPs associated with drug response.

The PG500 series : novel heparan sulfate mimetics as potent angiogenesis and heparanase inhibitors for cancer therapy

Heparan sulfate mimetics, which we have called the PG500 series, have been developed to target the inhibition of both angiogenesis and heparanase activity. This series extends the technology underpinning PI-88, a mixture of highly sulfated oligosaccharides which reached Phase III clinical development for hepatocellular carcinoma. Advances in the chemistry of the PG500 series provide numerous advantages over PI-88. These new compounds are fully sulfated, single entity oligosaccharides attached to a lipophilic moiety, which have been optimized for drug development. The rational design of these compounds has led to vast improvements in potency compared to PI-88, based on in vitro angiogenesis assays and in vivo tumor models. Based on these and other data, PG545 has been selected as the lead clinical candidate for oncology and is currently undergoing formal preclinical development as a novel treatment for advanced cancer.

Ghrelin gene-related peptides : multifunctional endocrine/autocrine modulators in health and disease

Ghrelin is a multi-functional peptide hormone which affects various processes including growth hormone and insulin release, appetite regulation, gut motility, metabolism and cancer cell proliferation. Ghrelin is produced in the stomach and in other normal and pathological cell types. It may act as an endocrine or autocrine/paracrine factor. The ghrelin gene encodes a precursor protein, preproghrelin, from which ghrelin and other potentially active peptides are derived by alternative mRNA splicing and/or proteolytic processing. The metabolic role of the peptide obestatin, derived from the preproghrelin C-terminal region, is controversial. However, it has direct effects on cancer cell proliferation. The regulation of ghrelin expression and the mechanisms through which the peptide products arise are unclear. We have recently re-examined the organisation of the ghrelin gene and identified several novel exons and transcripts. One transcript, which lacks the ghrelin-coding region of preproghrelin, contains the coding sequence of obestatin. Furthermore, we have identified an overlapping gene on the antisense strand of ghrelin, GHRLOS, which generates transcripts that may function as non-coding regulatory RNAs or code for novel, short bioactive peptides. The identification of these novel ghrelin-gene related transcripts and peptides raises critical questions regarding their physiological function and their role in obesity, diabetes and cancer.

The Kava Anxiety Depression Spectrum Study (KADSS): A randomized, placebo-controlled, cross-over trial using an aqueous extract of Piper methysticum.

Rationale: Piper methysticum (Kava) has been withdrawn in European, British, and Canadian markets due to concerns over hepatotoxic reactions. The WHO recently recommended research into “aqueous” extracts of Kava. Objective: The objective of this study was to conduct the first documented human clinical trial assessing the anxiolytic and antidepressant efficacy of an aqueous extract of Kava. Design and participants: The Kava Anxiety Depression Spectrum Study was a 3-week placebo-controlled, double-blind crossover trial that recruited 60 adult participants with 1 month or more of elevated generalized anxiety. Five Kava tablets per day were prescribed containing 250 mg of kavalactones/day. Results: The aqueous extract of Kava reduced participants' Hamilton Anxiety Scale score in the first controlled phase by −9.9 (CI = 7.1, 12.7) vs. −0.8 (CI = −2.7, 4.3) for placebo and in the second controlled phase by −10.3 (CI = 5.8, 14.7) vs. +3.3 (CI = −6.8, 0.2). The pooled effect of Kava vs. placebo across phases was highly significant (p < 0.0001), with a substantial effect size (d = 2.24, η² [sub]p[sub] = 0.428). Pooled analyses also revealed highly significant relative reductions in Beck Anxiety Inventory and Montgomery–Asberg Depression Rating Scale scores. The aqueous extract was found to be safe, with no serious adverse effects and no clinical hepatotoxicity. Conclusions: The aqueous Kava preparation produced significant anxiolytic and antidepressant activity and raised no safety concerns at the dose and duration studied. Kava appears equally effective in cases where anxiety is accompanied by depression. This should encourage further study and consideration of globally reintroducing aqueous rootstock extracts of Kava for the management of anxiety.

Exercise alone is not enough : weight loss also needs a healthy (Mediterranean) diet?

Objective: In the majority of exercise intervention studies, the aggregate reported weight loss is often small. The efficacy of exercise as a weight loss tool remains in question. The aim of the present study was to investigate the variability in appetite and body weight when participants engaged in a supervised and monitored exercise programme. ---------- Design: Fifty-eight obese men and women (BMI = 31·8 ± 4·5 kg/m2) were prescribed exercise to expend approximately 2092 kJ (500 kcal) per session, five times a week at an intensity of 70 % maximum heart rate for 12 weeks under supervised conditions in the research unit. Body weight and composition, total daily energy intake and various health markers were measured at weeks 0, 4, 8 and 12. ---------- Results: Mean reduction in body weight (3·2 ± 1·98 kg) was significant (P < 0·001); however, there was large individual variability (−14·7 to +2·7 kg). This large variability could be largely attributed to the differences in energy intake over the 12-week intervention. Those participants who failed to lose meaningful weight increased their food intake and reduced intake of fruits and vegetables. ---------- Conclusion: These data have demonstrated that even when exercise energy expenditure is high, a healthy diet is still required for weight loss to occur in many people.

Who and Why? Demographic and psychographic differences between consumers who have altered their shopping behaviour during a recession and those who have not

Research suggests that people differ in terms of changing their shopping behaviour during a recession. This paper reports on a preliminary descriptive study assessing what influences those consumers who have altered their shopping behaviour during such times. Driving the alteration of shopping behaviour were both demographic (age, gender, education, and nationality) and psychographic variables (attitudes, and head vs. heart decision making). Overall, the findings show that there are statistically significant differences between the two groups’ that marketers can address in their marketing strategies during the recession.

Volunteer visibility : what and how Australian not-for-profit organisations report volunteer contributions

The enhanced social profile of not-for-profit organisations (NFPs) and the role of volunteers have resulted in calls for NFPs to be more accountable and to disclose information relating to such contributions. In this study we identify, locate and categorise the extent of disclosures made in relation to volunteer contributions. We find that disclosure was more prevalent on NFP websites compared to digital annual report disclosures. We find that more NFPs provided disclosure on the activities of their volunteers than other items pertaining to volunteers. The valuation of volunteer contributions was the least likely to be disclosed. The findings contribute to international debate over the inclusion of volunteer contributions in the assessment of a NFP’s accountability over its resources and ultimately the enhancement of its sustainability.

Communicating assessment criteria is not sufficient for influencing students' approaches to assessment tasks – perspectives from a differential equations class

This report presents the findings of an exploratory study into the perceptions held by students regarding the use of criterion-referenced assessment in an undergraduate differential equations class. Students in the class were largely unaware of the concept of criterion referencing and of the various interpretations that this concept has among mathematics educators. Our primary goal was to investigate whether explicitly presenting assessment criteria to students was useful to them and guided them in responding to assessment tasks. Quantitative data and qualitative feedback from students indicates that while students found the criteria easy to understand and useful in informing them as to how they would be graded, the manner in which they actually approached the assessment activity was not altered as a result of the use of explicitly communicated grading criteria.

Strategic issues for the Not-for-profit sector

Bringing together some of Australia’s leading and emerging researchers studying different aspects of the not-for-profit (NFP) sector, Strategic Issues in the Not-for-Profit Sector draws on original Australian and comparative research to provide a spirited exploration of strategic issues facing NFP organisations. A diverse, vital and ever-growing sector in Australia, the NFP sector provides the organisational framework through which many of the most disadvantaged in the community receive access to services and support. However, pressures such as a changing composition, an erosion of financial sustainability, the need to professionalise, and demographic trends affecting patterns of volunteering have put pressure on the NFP sector to innovate and grow in new directions. Strategic Issues in the Not-for-Profit Sector considers the local and global drivers of change, as well as the industry, policy and community imperatives impacting upon NFP sustainability, providing a unique insight into not only the strategic issues, but also strategic responses emerging within the sector.

Not-for-profits and risk accountability : insuring the third sector

Not for profit organisations face significant challenges in managing organisational risk. In this regard not-for-profits are not unique but they are distinguishable from their 'for-profit' counterparts in that they are less likely to have the resources to find sufficient risk management strategies and plans, are very vunerable to cyclical changes in the insurance market and are not usually in a position to pass on the costs of increased premiums to third parties such as consumers of their services. This article explores the nature and extent of risks faced by the not-for-profit sector; the appropriateness and scope of risk management to reduce and manage the likelihood and incidence of risk; and the types of insurance and options to cover risks that materialise. It concludes with a recommendation for a potential course of action.