New insights into the FLPergic complements of parasitic nematodes: Informing deorphanisation approaches

FMRFamide-like peptide (FLP) receptors are appealing as putative anthelmintic targets. To date, 31 flp-encoding genes have been identified in Caenorhabditis elegans and thirteen FLP-activated G-protein coupled receptors (FLP-GPCRs) have been reported. The lack of knowledge on FLPs and FLP-GPCRs in parasites impedes their functional characterisation and chemotherapeutic exploitation. Using homology-based BLAST searches and phylogenetic analyses this study describes the identification of putative flp and flp-GPCR gene homologues in 17 nematode parasites providing the first pan-phylum genome-based overview of the FLPergic complement. These data will facilitate FLP-receptor deorphanisation efforts in the quest for novel control targets for nematode parasites.

MErCuRIC1: A Phase I study of MEK1/2 inhibitor PD-0325901 with cMET inhibitor crizotinib in RASMT and RASWT (with aberrant c-MET) metastatic colorectal cancer (mCRC) patients.

Background: RAS is mutated (RASMT) in ~55% of mCRC, and phase III studies have shown that patients harbouring RAS mutations do not benefit from anti-EGFR MoAbs. In addition, ~50% of RAS Wild Type (RASWT) will not benefit from the addition of an EGFR MoAb to standard chemotherapy. Hence, novel treatment strategies are urgently needed for RASMT and > 50% of RASWT mCRC patients. c-MET is overexpressed in ~50-60%, amplified in ~2-3% and mutated in ~3-5% of mCRC. Recent preclinical studies have shown that c-MET is an important mediator of resistance to MEK inhibitors (i) in RASMT mCRC, and that combined MEKi/METi resulted in synergistic reduction in tumour growth in RASMT xenograft models (1). A number of recent studies have highlighted the role of c-MET in mediating primary/secondary resistance to anti-EGFR MoAbs in mCRC, suggesting that patient with RASWT tumours with aberrant c-MET (RASWT/c-MET+) may benefit from anti-c-MET targeted therapies (2). These preclinical data supported the further clinical evaluation of combined MEKi/METi treatment in RASMT and RASWT CRC patients with aberrant c-MET signalling (overexpression, amplification or mutation; RASWT/c-MET+). Methods: MErCuRIC1 is a phase I combination study of METi crizotinib with MEKi PD-0325901. The dose escalation phase, utilizing a rolling six design, recruits 12-24 patients with advanced solid tumours and aims to assess safety/toxicity of combination, recommended phase II (RPII) dose, pharmacokinetics (PK) and pharmacodynamics (PD) (pERK1/2 in PBMC and tumour; soluble c-MET). In the dose expansion phase an additional 30-42 RASMT and RASWT/c-MET mCRC patients with biopsiable disease will be treated at the RPII dose to further evaluate safety, PK, PD and treatment response. In the dose expansion phase additional biopsy and blood samples will be obtained to define mechanisms of response/resistance to crizotinib/PD-0325901 therapy. Enrolment into the dose escalation phase began in December 2014 with cohort 1 still ongoing. EudraCT registry number: 2014-000463-40. (1) Van Schaeybroeck S et al. Cell Reports 2014;7(6):1940-55; (2) Bardelli A et al. Cancer Discov 2013;3(6):658-73. Clinical trial information: 2014-000463-40.

High-Resolution Microwave Near-Field Imaging Using Resonance Probes

A novel microwave high-resolution near-field imaging technique is proposed and experimentally evaluated in reflectometry imaging scenarios involving planar metal-dielectric structures. Two types of resonance near field probes-a small helix antenna and a loaded subwavelength slot aperture are studied in this paper. These probes enable very tight spatial field localization with the full width at half maximum around one tenth of a wavelength, λ, at λ/100-λ/10 standoff distance. Importantly, the proposed probes permit resonance electromagnetic coupling to dielectric or printed conductive patterns, which leads to the possibility of very high raw image resolution with imaged feature-to-background contrast greater than 10-dB amplitude and 50° phase. In addition, high-resolution characterization of target geometries based on the cross correlation image processing technique is proposed and assessed using experimental data. It is shown that printed elements features with subwavelength size ~λ/15 or smaller can be characterized with at least 10-dB resolution contrast.

The role lipid aldehydes and ALEs in the pathogenesis of diabetic retinopathy

Distant activity of 67P/Churyumov-Gerasimenko in 2014: Ground-based results during the Rosetta pre-landing phase

As the ESA Rosetta mission approached, orbited, and sent a lander to comet 67P/Churyumov-Gerasimenko in 2014, a large campaign of ground-based observations also followed the comet. We constrain the total activity level of the comet by photometry and spectroscopy to place Rosetta results in context and to understand the large-scale structure of the comet's coma pre-perihelion. We performed observations using a number of telescopes, but concentrate on results from the 8m VLT and Gemini South telescopes in Chile. We use R-band imaging to measure the dust coma contribution to the comet's brightness and UV-visible spectroscopy to search for gas emissions, primarily using VLT/FORS. In addition we imaged the comet in near-infrared wavelengths (JHK) in late 2014 with Gemini-S/Flamingos 2. We find that the comet was already active in early 2014 at heliocentric distances beyond 4 au. The evolution of the total activity (measured by dust) followed previous predictions. No gas emissions were detected despite sensitive searches. The comet maintains a similar level of activity from orbit to orbit, and is in that sense predictable, meaning that Rosetta results correspond to typical behaviour for this comet. The gas production (for CN at least) is highly asymmetric with respect to perihelion, as our upper limits are below the measured production rates for similar distances post-perihelion in previous orbits.

Peer tutoring in a medical school: perceptions of tutors and tutees

Background: Peer tutoring has been described as “people from similar social groupings who are not professional teachers helping each other to learn and learning themselves by teaching”. Peer tutoring is well accepted as a source of support in many medical curricula, where participation and learning involve a process of socialisation.
Peer tutoring can ease the transition of the junior students from the university class environment to the hospital workplace. In this paper, we apply the Experienced Based Learning (ExBL) model to explore medical students’ perceptions of their experience of taking part in a newly established peer tutoring program at a hospital based
clinical school.
Methods: In 2014, all students at Sydney Medical School – Central, located at Royal Prince Alfred Hospital were invited to voluntarily participate in the peer tutoring program. Year 3 students (n = 46) were invited to act as tutors for Year 1 students (n = 50), and Year 4 students (n = 60) were invited to act as tutors for Year 2 students (n = 51). Similarly, the ‘tutees’ were invited to take part on a voluntary basis. Students were invited to attend focus groups, which were held at the end of the program. Framework analysis was used to code and categorise data into themes.
Results: In total, 108/207 (52 %) students participated in the program. A total of 42/106 (40 %) of Year 3 and 4 students took part as tutors; and of 66/101 (65 %) of Year 1 and 2 students took part as tutees. Five focus groups were held, with 50/108 (46 %) of students voluntarily participating. Senior students (tutors) valued the opportunity to practice and improve their medical knowledge and teaching skills. Junior students (tutees) valued the opportunity for additional practice and patient interaction, within a relaxed, small group learning environment.
Conclusion: Students perceived the peer tutoring program as affording opportunities not otherwise available within the curriculum. The peer teaching program provided a framework within the medical curriculum for senior students to practice and improve their medical knowledge and teaching skills. Concurrently, junior students were provided with a valuable learning experience that they reported as being qualitatively different to traditional teaching by faculty.

Molecular mechanisms mediating the beneficial metabolic effects of [Arg4]tigerinin-1R in mice with diet-induced obesity and insulin resistance

The frog skin host-defense peptide tigerinin-1R stimulates insulin release in vitro and improves glucose tolerance and insulin sensitivity in animal models of type 2 diabetes. This study extends these observation by investigating the molecular mechanisms of action underlying the beneficial metabolic effects of the analogue [Arg4]tigerinin-1R in mice with diet induced obesity, glucose intolerance and insulin resistance. The study also investigates the electrophysiological effects of the peptide on KATP and L-type Ca2+ channels in BRINBD11 clonal β cells. Non-fasting plasma glucose and glucagon concentrations were significantly (P<0.05) decreased and plasma insulin increased by twice daily treatment with [Arg4]tigerinin-1R (75 nmol.kg-1 body weight) for 28 days. Oral and intraperitoneal glucose tolerance were significantly (P < 0.05) improved accompanied by enhanced secretion and action of insulin. The peptide blocked KATP channels and, consistent with this, improved beta cell responses of isolated islets to a range of secretagogues. Peptide administration resulted in up-regulation of key functional genes in islets involved insulin secretion (Abcc8, Kcnj11, Cacna1c and Slc2a2) and in skeletal muscle involved with insulin action (Insr, Irs1, Pdk1, Pik3ca, and Slc2a4). These observations encourage further development of tigerinin-1R analogues for the treatment of patients with type 2 diabetes.

Principles of fatigue in residency education: a qualitative study

Background: Proposals to implement fatigue-management strategies in residency education assume that medicine shares the view
of other risk-adverse industries that fatigue is hazardous. This view is an essential underpinning of fatigue-management strategies
that other industries have embedded as part of their workplace occupational health and safety programs. We sought to explore how
residents understand fatigue in the context of their training environment.

Methods: We interviewed 21 residents in 7 surgical and nonsurgical programs at Western University in 2014. All participants met the
inclusion criteria of routinely working 24-hour call shifts while enrolled in their training program. Data collection and analysis occurred iteratively in keeping with constructivist grounded theory methodology and informed theoretical sampling to sufficiency.

Results: Four predominant principles of fatigue captured how the social learning environment shaped residents’ perceptions of
fatigue. These included the conceptualization of fatigue as (a) inescapable and therefore accepted, (b) manageable through experience, (c) necessary for future practice and (d) surmountable when required.

Interpretation: This study elaborates our understanding of how principles of fatigue are constructed and reinforced by the training
environment. Whereas fatigue is seen as a collective hazard in other industries, our data showed that, in residency training, fatigue
may be seen as a personal challenge. Consequently, fatigue-management strategies that conceptualize fatigue as an occupational
threat may have a limited impact on resident behaviour and patient safety.