Tissue-engineered 3D tumor angiogenesis models : potential technologies for anti-cancer drug discovery

Angiogenesis is indispensable for solid tumor expansion, and thus it has become a major target of cancer research and anti-cancer therapies. Deciphering the arcane actions of various cell populations during tumor angiogenesis requires sophisticated research models, which could capture the dynamics and complexity of the process. There is a continuous need for improvement of existing research models, which engages interdisciplinary approaches of tissue engineering with life sciences. Tireless efforts to develop a new model to study tumor angiogenesis result in innovative solutions, which bring us one step closer to decipher the dubious nature of cancer. This review aims to overview the recent developments, current limitations and future challenges in three-dimensional tissue-engineered models for the study of tumor angiogenesis and for the purpose of elucidating novel targets aimed at anti-cancer drug discovery.

Delivering crushed tablets using thickened fluids : is drug diffusion into gastric fluids restricted?

Solid medications are often crushed and mixed with food or thickened water to aid drug delivery for those who cannot or prefer not to swallow whole tablets or capsules. Dysphagic patients have the added problem of being unable to safely swallow thin fluids so water thickened with polysaccharides is used to deliver crushed medications and ensure safe swallowing. It is postulated that these polysaccharide systems may restrict drug release by reducing the diffusion of the drug into gastric fluids. METHODS By using a vertical diffusion cell separated with a synthetic membrane, the diffusion of a model drug (atenolol) was studied from a donor system containing the drug dispersed into thickened water with xanthan gum (concentration range from 0.005%-2.2%) into a receptor system containing simulated gastric fluid (SGF) at 37°C. The amount of drug transferred was measured over 8 hours and diffusion coefficients estimated using the Higuchi model approach. RESULTS Atenolol diffusion decreased with increasing xanthan gum concentration up to 1.0%, above which diffusion remained around 300 μ2s-1. The rheological measurements captured the influence of the structure and conformation of the polysaccharide in water on the movement and availability of the drug in SGF. DISCUSSION Dose form administration for dysphagic patients’ needs special attention from general practitioners, pharmacist and patients. Improving drug release of crushed tablets from thickening agents requires a reduction in the diffusion pathway (e.g. by decreasing drop size radius). This approach could make the drug available in SGF in a short time without compromising the mechanical aspects of thickening agents that guarantee safe swallowing.

Incidence and fatality of serious suicide attempts in a predominantly rural population in Shandong, China : a public health surveillance study

Objectives To estimate the incidence of serious suicide attempts (SSAs, defined as suicide attempts resulting in either death or hospitalisation) and to examine factors associated with fatality among these attempters. Design A surveillance study of incidence and mortality. Linked data from two public health surveillance systems were analysed. Setting Three selected counties in Shandong, China. Participants All residents in the three selected counties. Outcome measures Incidence rate ( per 100 000 person-years) and case fatality rate (%). Methods Records of suicide deaths and hospitalisations that occurred among residents in selected counties during 2009–2011 (5 623 323 person-years) were extracted from electronic databases of the Disease Surveillance Points (DSP) system and the Injury Surveillance System (ISS) and were linked by name, sex, residence and time of suicide attempt. A multiple logistic regression model was developed to examine the factors associated with a higher or lower fatality rate. Results The incidence of SSAs was estimated to be 46 (95% CI 44 to 48) per 100 000 person-years, which was 1.5 times higher in rural versus urban areas, slightly higher among females, and increased with age. Among all SSAs, 51% were hospitalised and survived, 9% were hospitalised but later died and 40% died with no hospitalisation. Most suicide deaths (81%) were not hospitalised and most hospitalised SSAs (85%) survived. The fatality rate was 49% overall, but was significantly higher among attempters living in rural areas, who were male, older, with lower education or with a farming occupation. With regard to the method of suicide, fatality was lowest for non-pesticide poisons (7%) and highest for hanging (97%). Conclusions The incidence of serious suicide attempts is substantially higher in rural areas than in urban areas of China. The risk of death is influenced by the attempter’s sex, age, education level, occupation, method used and season of year.

Sortase A : an ideal target for anti-virulence drug development

Sortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and biofilm formation. The additional properties of sortase A as an enzyme that is not required for Gram-positive bacterial growth or viability and is conveniently located on the cell membrane making it more accessible to inhibitor targeting, constitute additional reasons reinforcing the view that sortase A is an ideal target for anti-virulence drug development. Many inhibitors of sortase A have been identified to date using high-throughput or in silico screening of compound libraries (synthetic or natural), and while many have proved useful tools for probing the action model of the enzyme, several are also promising candidates for the development into potent inhibitors. This review is focused on the most promising sortase A inhibitor compounds that are currently in development as leads towards a new class of anti-infective drugs that are urgently needed to help combat the alarming increase in antimicrobial resistance.

Antidepressant direct-to-consumer prescription drug advertising and public stigma of depression : the mediating role of perceived prevalence of depression

This study examines whether memory of antidepressant direct-to-consumer (DTC) prescription drug advertising is associated with the public stigma attached to depression. Results indicate that those who better remember antidepressant DTC ads tend to have a higher perceived prevalence of depression (i.e., more people suffer from depression). And, the perceived prevalence of depression is inversely associated with the public stigma toward depression. That is, those who have a higher perceived prevalence of depression report that they are more supportive of and comfortable with people who have depression. The results suggest that the perceived prevalence of depression is a mediating variable that accounts for the relationship between memory of antidepressant DTC ads and the public stigma toward depression. The implications and limitations of the study, as an exploratory investigation, are discussed.

Using DNA as a drug - bioprocessing and delivery strategies

DNA may take a leading role in a future generation of blockbuster therapeutics. DNA has inherent advantages over other biomolecules such as protein, RNA and virus-like particles including safety, production simplicity and higher stability at ambient temperatures. Vaccination is the principal measure for preventing influenza and reducing the impact of pandemics; however, vaccines take up to 8-9 months to produce, and the global production capacity is woefully low. With production times as short as 2 weeks, improved safety and stability, bioprocess engineering developments, and the ability to perform numerous therapeutic roles, DNA has the potential to meet the demands of emerging and existing diseases. DNA is experiencing sharp growths in demand as indicated by its use in gene therapy trials and DNA vaccine related patents. Of particular interest for therapeutic use is plasmid DNA (pDNA), a form of non-genomic DNA that makes use of cellular machinery to express proteins or antigens. The production stages of fermentation and downstream purification are considered in this article. Forward looking approaches to purifying and delivering DNA are reported, including affinity chromatography and nasal inhalation. The place that pDNA may take in the preparation for and protection against pandemics is considered. If DNA therapeutics and vaccines prove to be effective, the ultimate scale of production will be huge which shall require associated bioprocess engineering research and development for purification of this large, unique biomolecule.

Using DNA as a drug : challenges and opportunities for process engineers

The maturing of the biotechnology industry and a focus on productivity has seen a shift from discovery science to small-scale bench-top research to higher productivity, large scale production. Health companies are aggressively expanding their biopharmaceutical interests, an expansion which is facilitated by biochemical and bioprocess engineering. An area of continuous growth is vaccines. Vaccination will be a key intervention in the case of an influenza pandemic. The global manufacturing capacity for fast turn around vaccines is currently woefully inadequate at around 300 million shots. As the prevention of epidemics requires > 80 % vaccination, in theory the world should currently be aiming for the ability to produce around 5.3 billion vaccines. Presented is a production method for the creation of a fast turn around DNA vaccine. A DNA vaccine could have a production time scale of as little as two weeks. This process has been harnessed into a pilot scale production system for the creation of a pre-clinical grade malaria vaccine in a collaborative project with the Coppel Lab, Department of Microbiology, Monash University. In particular, improvements to the fermentation, chromatography and delivery stages will be discussed. Consideration will then be given as to how the fermentation stage affects the mid and downstream processing stages.

Are road traffic crash fatality rates converging among OECD countries?

This article examines the trends of road traffic crash (RTC) fatality rates in OECD countries over the past four decades. Based on recent developments in the economic growth literature we propose and test the hypothesis that RTC fatality rates initially increase with economic development, peak, and then gradually decrease. The theory predicts that, as a result, the RTC fatality rates of different countries will tend to converge over time. Our results for the period 1961–2007 reveal no evidence of the convergence of RTC fatality rates across the OECD as a whole for that time period. Nevertheless, there is evidence of convergence among sub-groups of countries. This evidence may assist policymakers as an additional way of benchmarking their country's performance against that of its peers and to identify the next-closest peer in country sub-groups with superior road safety performance.

Employee perceptions of alcohol and drug policy effectiveness: Policy features, concerns about drug testing, and the key role of preventative measures

As negative employee attitudes towards alcohol and other drug (AOD) policies may have serious consequences for organizations, the present study examined demographic and attitudinal dimensions leading to employees’ perceptions of AOD policy effectiveness. Survey responses were obtained from 147 employees in an Australian agricultural organization. Three dimensions of attitudes towards AOD policies were examined: knowledge of policy features, attitudes towards testing, and preventative measures such as job design and organizational involvement in community health. Demographic differences were identified, with males and blue-collar employees reporting significantly more negative attitudes towards the AOD policy. Attitude dimensions were stronger predictors of perceptions of policy effectiveness than demographics, and the strongest predictor was preventative measures. This suggests that organizations should do more than design adequate and fair AOD policies, and take a more holistic approach to AOD impairment by engaging in workplace design to reduce AOD use and promote a consistent health message to employees and the community.

Deterrence of drug driving: The impact of the ACT drug driving legislation and detection techniques

The study sought to explore the initial impact of the ACT's implementation of roadside oral fluid drug screening program. The results suggest that a number of individuals reported intentions to drug drive in the future. The classical deterrence theory variables of certainty of apprehension, severity and swiftness of sanctions were not predictive of intentions to drug drive in the future. In contrast, having avoided apprehension and having known of others that have avoided apprehension were predictive of intentions to drug drive in the future. Increasing perceptions of the certainty of apprehension, increased testing frequency, and increased awareness of the oral fluid drug screening program could potentially lead to reductions of drug driving and result in safer road environment for all ACT community members.

A review and comparative analysis of international drug driving policies. Report to the New South Wales (NSW) Centre for Road Safety

The New South Wales (NSW) Centre for Road Safety (CRS) called for research services to conduct a review of international policy and practice to address drug-driving. The project sought to provide Transport for NSW (TfNSW) with a comprehensive review of current and emerging international practices in this area1. This report is submitted by the Centre for Accident Research and Road Safety – Queensland (CARRS-Q)...

The culture of young women's drinking: Implications for developing effective policing strategies. Report to National Drug Strategy Law Enforcement Committee

Alcohol-related mortality and morbidity represents a substantial financial burden on communities across the world. Adolescence and young adulthood is a peak period for heavy episodic alcohol consumption, with over a third of all people aged 14-19 years having been at risk of acute alcoholrelated harm at least once in the previous 12 months (Australian Institute of Health and Welfare [AIHW], 2011). Excessive alcohol consumption has long been seen as a male problem; however, a gradual shift towards a social acceptance of female drunkenness has narrowed the gap in drinking quantity and style between men and women (Grucza, Bucholz, Rice, & Bierut, 2008). The presented data point to the vulnerability of women to the consequences of acute alcohol intoxication and indicate that alcohol-related offending by women is on the rise. Taken together, these findings reveal that alcohol-related harms and aggression for young women are becoming more prevalent and problematic. This report addressed these issues from a policing perspective...

Drug administration guides in dysphagia

Aim: The aim of this evaluation was to evaluate the use of Individualised Medication Administration Guides (IMAGs) for patients with dysphagia on one stroke ward over a 6month period. Background: Patients with dysphagia (PWD) are more likely to suffer an administration error than patients without swallowing difficulties. To both standardise and improve medicines administration to patients with dysphagia I-MAGs were introduced on one stroke ward over a 6 month period. Methods: A software package supported with data on current national guidelines on the administration of medicines to PWD was designed by a specialised pharmacist in dysphagia to enable him to create individualised medication administration guides for patients with dysphagia which stated how each medicine should be optimally prepared and administered. On completion of the pilot service a questionnaire was given to all nurses, pharmacist and speech and language therapists who had experienced the I-MAGs. All the professionals received the same questionnaire but questions relevant only to their practice were added to the nurse’s questionnaire. Results: Of 26 Healthcare professionals (HCPs) approached, 19 returned completed questionnaires. Higher variability was found in the 13 responses from the nurse respondents than in the ones from the 3 pharmacist and the 3 SALTs. 8 (61%) of the nurses felt more confident in their practice when I-MAGs were in place. 10 (76%) of the nurses admitted that the guides could sometimes increase the time of the administration, but saw that it made practice safer. All the pharmacists considered the recommendations in the guides useful and all the respondents with the exception of one nurse (12:13) would like this service to continue. Conclusion: I-MAGs were well received on the ward and they support individualised care for patients with dysphagia. But the guides needed additional pharmacist input and greater nursing time. Research to determine the cost effectiveness of I-MAGs is needed.

Where to after Drink Rite: An evaluation of opportunities for police and community promotion of an anti-drink driving message in the licensed venue setting. Report to the National Drug Strategy Law Enforcement Funding Committee

Estimating the prevalence of drink driving is a difficult task. Self‐reported drink driving indicates that drink driving is far more common than official statistics suggest. In order to promote a responsible attitude towards alcohol consumption and drink driving within the Queensland community, the Queensland Police Service, Queensland Health and Queensland Transport developed the ‘Drink Rite’ program (Queensland Police Service information sheet, 2009). However, the feasibility of the program is now in doubt as the National Health and Medical Research Council’s guidelines for alcohol consumption changed in 2009 to state “For healthy men and women, drinking no more than four standard drinks on a single occasion reduces the risk of alcohol‐related injury arising from that occasion” (NHMRC Publication, 2009, p. 51). As such, adhering to the NHMRC guidelines places restrictions on how the existing Drink Rite program can be operated (i.e. by reducing the number of standard drinks provided to participants from eight to four). It is arguable that a reduction in the number of alcoholic drinks provided to participants in the program will result in a large reduction in observed BAC readings. This, in turn, will lead to a potential loss of message content when discussing the variation in the effects of alcohol.

Stimulation of osteogenesis and angiogenesis of hBMSCs by delivering Si ions and functional drug from mesoporous silica nanospheres

Multifunctional bioactive materials with the ability to stimulate osteogenesis and angiogenesis of stem cells play an important role in the regeneration of bone defects. However, how to develop such biomaterials remains a significant challenge. In this study, we prepared mesoporous silica nanospheres (MSNs) with uniform sphere size (∼90 nm) and mesopores (∼2.7 nm), which could release silicon ions (Si) to stimulate the osteogenic differentiation of human bone marrow stromal cells (hBMSCs) via activating their ALP activity, bone-related gene and protein (OCN, RUNX2 and OPN) expression. Hypoxia-inducing therapeutic drug, dimethyloxaloylglycine (DMOG), was effectively loaded in the mesopores of MSNs (D-MSNs). The sustained release of DMOG from D-MSNs could stabilize HIF-1α and further stimulated the angiogenic differentiation of hBMSCs as indicated by the enhanced VEGF secretion and protein expression. Our study revealed that D-MSNs could combine the stimulatory effect on both osteogenic and angiogenic activity of hBMSCs. The potential mechanism of D-MSN-stimulated osteogenesis and angiogenesis was further elucidated by the supplementation of cell culture medium with pure Si ions and DMOG. Considering the easy handling characteristics of nanospheres, the prepared D-MSNs may be applied in the forms of injectable spheres for minimally invasive surgery, or MSNs/polymer composite scaffolds for bone defect repair. The concept of delivering both stimulatory ions and functional drugs may offer a new strategy to construct a multifunctional biomaterial system for bone tissue regeneration.