Solid phase synthesis of Smac/DIABLO-derived peptides using a 'Safety-Catch' resin:Identification of potent XIAP BIR3 antagonists

The N-terminal sequence of the Smac/DIABLO protein is known to be involved in binding to the BIR3 domain of the anti-apoptotic proteins IAPs, antagonizing their action. Short peptides and peptide mimetics based on the first 4-residues of Smac/DIABLO have been demonstrated to re-sensitize resistant cancer cells, over-expressing IAPs, to apoptosis. Based on the well-defined structural basis for this interaction, a small focused library of C-terminal capped Smac/DIABLO-derived peptides was designed in silico using docking to the XIAP BIR3 domain. The top-ranked computational hits were conveniently synthesized employing Solid Phase Synthesis (SPS) on an alkane sulfonamide 'Safety-Catch' resin. This novel approach afforded the rapid synthesis of the target peptide library with high flexibility for the introduction of various C-terminal amide-capping groups. The library members were obtained in high yield (>65%) and purity (>85%), upon nucleophilic release from the activated resin by treatment with various amine nucleophiles. In vitro caspase-9 activity reconstitution assays of the peptides in the presence of the recombinant BIR3-domain of human XIAP (500nM) revealed N-methylalanyl-tertiarybutylglycinyl-4-(R)-phenoxyprolyl-N-biphenylmethyl carboxamide (11a) to be the most potent XIAP BIR3 antagonist of the series synthesized inducing 93% recovery of caspase-9 activity, when used at 1µM concentration. Compound (11a) also demonstrated moderate cytotoxicity against the breast cancer cell lines MDA-MB-231 and MCF-7, compared to the Smac/DIABLO-derived wild-type peptide sequences that were totally inactive in the same cell lines.

The Disrupted Space: Safety and Security in traditional contexts

One of the core elements of successful planning is the individuals’ experience of their shared open spaces. This paper attributes to the relationship between safety and urban design by means of natural surveillance and security in the city’s shared spaces. It examines how political claims over space reassembled alternative definitions of security in one of Cairo’s oldest quarters, and how ambitious planning schemes were mostly driven by problems of insecurity, chaos and disorder. The main crux to this account is based on original documents, interviews and maps which reveals considerable insights and accounts of how this vision affected the quarter’s spatial quality and the user’s reactions to his new spatial formula. It also reveals conflicting conceptions of safety and security between the planning ambitions and the users experiences, which not only lacked reliable visions for securing the quarter, but also resulted further disruption to their everyday living spaces.

Hydrogel-forming microneedle arrays exhibit antimicrobial properties:potential for enhanced patient safety

We describe, for the first time, the microbial characterisation of hydrogel-forming polymeric microneedle arrays and the potential for passage of microorganisms into skin following microneedle penetration. Uniquely, we also present insights into the storage stability of these hydroscopic formulations, from physical and microbiological viewpoints, and examine clinical performance and safety in human volunteers. Experiments employing excised porcine skin and radiolabelled microorganisms showed that microorganisms can penetrate skin beyond the stratum corneum following microneedle puncture. Indeed, the numbers of microorganisms crossing the stratum corneum following microneedle puncture were greater than 105 cfu in each case. However, no microorganisms crossed the epidermal skin. When using a 21G hypodermic needle, more than 104 microorganisms penetrated into the viable tissue and 106 cfu of Candida albicans and Staphylococcus epidermidis completely crossed the epidermal skin in 24 h. The hydrogel-forming materials contained no microorganisms following de-moulding and exhibited no microbial growth during storage, while also maintaining their mechanical strength, apart from when stored at relative humidities of 86%. No microbial penetration through the swelling microneedles was detectable, while human volunteer studies confirmed that skin or systemic infection is highly unlikely when polymeric microneedles are used for transdermal drug delivery. Since no pharmacopoeial standards currently exist for microneedle-based products, the exact requirements for a proprietary product based on hydrogel-forming microneedles are at present unclear. However, we are currently working towards a comprehensive specification set for this microneedle system that may inform future developments in this regard.

Newly Acquired Fear of Falling Leads to Altered Eye Movement Patterns and Reduced Stepping Safety: A Case Study

This opportune case study describes visual and stepping behaviours of an 87 year old female (P8), both prior to, and following two falls. Before falling, when asked to walk along a path containing two stepping guides positioned before and after an obstacle, P8 generally visually fixated the first stepping guide until after foot contact inside it. However, after falling P8 consistently looked away from the stepping guide before completing the step into it in order to fixate the upcoming obstacle in her path. The timing of gaze redirection away from the target (in relation to foot contact inside it) correlated with absolute stepping error. No differences in eyesight, cognitive function, or balance were found between pre- and post-fall recordings. However, P8 did report large increases in fall-related anxiety and reduced balance confidence, supporting previously suggested links between anxiety/increased fear or falling and maladaptive visual/stepping behaviours. The results represent a novel insight into how psychological and related behavioural factors can change in older adults following a fall, and provide a possible partial rationalisation for why recent fallers are more likely to fall again in the following 12 months. These findings highlight novel possibilities for falls prevention and rehabilitation.

Risk assessment of neonatal excipient exposure:Lessons from food safety and other areas

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

Queer Spaces, Sexual Violence and the Desire for Safety

Queer politics and spaces have historically been associated with ideals of sexual liberation. They are conceptualised as spaces where sex, and its intersections with intimacy, friendship and love can be explored outside of normative frameworks which value monogamous reproductive heterosexuality at the expense of other non-normative sexual expressions. In recent years, however, autonomous queer spaces such as the global Queeruption gatherings and other queer community spaces in Australia have become increasingly concerned with the presence and danger of sexual violence in queer communities. Almost without exception, this danger has been responded to through the creation of ‘safe(r) spaces’ policies, generally consisting of a set of guidelines and proscribed behaviours which individuals must agree to in order to participate in or attend the event or space. The guidelines themselves tend to privilege of sexual politics of affirmative verbal consent, insisting that such consent should be sought prior to any physical or sexual contact, inferring that a failure to do so is ethically unacceptable within. This chapter reflects on the attempts to construct queer communities as ‘safer spaces,’ arguing that the concepts of consent and safety are inadequate to develop a queer response to sexual violence. Such a response, it argues, must be based on the openness to possibilities and refusal of sexual restrictions and regulations that have always been central elements of queer theory and politics.

Better together: Interprofessional Education in Medication Safety

Background: The importance of actively working with other professionals, as part of a single team, is well embedded in discussions relating to effective healthcare. The need for effective teamwork specifically in relation to patient safety is also widely acknowledged; however healthcare has traditionally been poor at building teams and professional groups tend to function semi-autonomously and autocratically.1
Objective: This study aims to gain the views and experiences of students from nursing, pharmacy and medicine involved in an interprofessional workshop in medication safety.
Setting and methods: Interprofessional workshops involving students from nursing, pharmacy and medicine were delivered using case studies involving medication incidents. Focus groups were used to investigate participant’s views and experiences of the workshop.
Results: Focus groups were completed with 22 students. Five main themes were identified from the focus group data relating to medication safety; these were increasing confidence, insight into roles, improving skills, culture of responsibility and application to future practice.
Conclusions: This study represents a model for delivery of training that has demonstrated improvement in the students’ attitudes towards team working and is a first step towards introducing team working into the medication safety program. The programme continues to run using live and virtual workshops.

1. Leape LL. A systems analysis approach to medical error. J Clin Eval Clin Pract. 1997. 3, 3, 213-222.

Successful Food Safety Analysis

Dr Kevin Cooper of the Institute for Global Food Security at Queen’s University Belfast, Northern Ireland, spoke to Kate Mosford of The
Column about the importance of accuracy, reliability, and stability in food safety analysis and the role of ultrahigh-pressure liquid chromatography tandem mass spectrometry (UHPLC–MS–MS) in his research.