The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study

Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCα), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies

The insecure airway: a comparison of knots and commercial devices for securing endotracheal tubes

BACKGROUND: Endotracheal Tubes (ETTs) are commonly secured using adhesive tape, cloth tape, or commercial devices. The objectives of the study were (1) To compare degrees of movement of ETTs secured with 6 different commercial devices and (2) To compare movement of ETTs secured with cloth tape tied with 3 different knots (hitches). METHODS: A 17 cm diameter PVC tube with 14 mm "mouth" hole in the side served as a mannequin. ETTs were subjected to repeated jerks, using a cable and pulley system. Measurements: (1) Total movement of ETTs relative to "mouth" (measure used for devices) (2) Slippage of ETT through securing knot (measure used for knots). RESULTS: Among commercial devices, the Dale(® )showed less movement than other devices, although some differences between devices did not reach significance. Among knots, Magnus and Clove Hitches produced less slippage than the Cow Hitch, but these differences did not reach statistical significance. CONCLUSION: Among devices tested, the Dale(® )was most secure. Within the scope offered by the small sample sizes, there were no statistically significant differences between the knots in this study

Methods for assessing DNA repair and repeat expansion in Huntington's Disease

Huntington’s disease (HD) is caused by a CAG repeat expansion in the HTT gene. Repeat length can change over time, both in individual cells and between generations, and longer repeats may drive pathology. Cellular DNA repair systems have long been implicated in CAG repeat instability but recent genetic evidence from humans linking DNA repair variants to HD onset and progression has reignited interest in this area. The DNA damage response plays an essential role in maintaining genome stability, but may also license repeat expansions in the context of HD. In this chapter we summarize the methods developed to assay CAG repeat expansion/contraction in vitro and in cells, and review the DNA repair genes tested in mouse models of HD. While none of these systems is currently ideal, new technologies, such as long-read DNA sequencing, should improve the sensitivity of assays to assess the effects of DNA repair pathways in HD. Improved assays will be essential precursors to high-throughput testing of small molecules that can alter specific steps in DNA repair pathways and perhaps ameliorate expansion or enhance contraction of the HTT CAG repeat

A new era for understanding amyloid structures and disease

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention

Development of a System for the Study of Protein-Protein Interactions in Planta : Characterization of a TATA-Box Binding Protein Complex in Oryza sativa

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Can the Reboot coaching programme support critical care nurses in coping with stressful clinical events? A mixed-methods evaluation assessing resilience, burnout, depression and turnover intentions.

BackgroundCritical care nurses (CCNs) are routinely exposed to highly stressful situations, and at high-risk of suffering from work-related stress and developing burnout. Thus, supporting CCN wellbeing is crucial. One approach for delivering this support is by preparing CCNs for situations they may encounter, drawing on evidence-based techniques to strengthen psychological coping strategies. The current study tailored a Resilience-boosting psychological coaching programme [Reboot] to CCNs. Other healthcare staff receiving Reboot have reported improvements in confidence in coping with stressful clinical events and increased psychological resilience. The current study tailored Reboot for online, remote delivery to CCNs (as it had not previously been delivered to nurses, or in remote format), to (1) assess the feasibility of delivering Reboot remotely, and to (2) provide a preliminary assessment of whether Reboot could increase resilience, confidence in coping with adverse events and burnout.MethodsA single-arm mixed-methods (questionnaires, interviews) before-after feasibility study design was used. Feasibility was measured via demand, recruitment, and retention (recruitment goal: 80 CCNs, retention goal: 70% of recruited CCNs). Potential efficacy was measured via questionnaires at five timepoints; measures included confidence in coping with adverse events (Confidence scale), Resilience (Brief Resilience Scale), depression (PHQ-9) and burnout (Oldenburg-Burnout-Inventory). Intention to leave (current role, nursing more generally) was measured post-intervention. Interviews were analysed using Reflexive Thematic Analysis.ResultsResults suggest that delivering Reboot remotely is feasible and acceptable. Seventy-seven nurses were recruited, 81% of whom completed the 8-week intervention. Thus, the retention rate was over 10% higher than the target. Regarding preliminary efficacy, follow-up measures showed significant increases in resilience, confidence in coping with adverse events and reductions in depression, burnout, and intention to leave. Qualitative analysis suggested that CCNs found the psychological techniques helpful and particularly valued practical exercises that could be translated into everyday practice.ConclusionThis study demonstrates the feasibility of remote delivery of Reboot and potential efficacy for CCNs. Results are limited due to the single-arm feasibility design; thus, a larger trial with a control group is needed

Crystallization and preliminary X-ray analysis of the human respiratory syncytial virus nucleocapsid protein

Crystals of the nucleocapsid protein of human respiratory syncytial virus have been obtained in two forms, the better of which diffracted to 3.6 Å resolution and contained ten subunits in the asymmetric unit