Polo like kinase 2 tumour suppressor and cancer biomarker: new perspectives on drug sensitivity/resistance in ovarian cancer

The polo-like kinase PLK2 has recently been identified as a potential theranostic marker in the management of chemotherapy sensitive cancers. The methylation status of the PLK2 CpG island varies with sensitivity to paclitaxel and platinum in ovarian cancer cell lines. Importantly, extrapolation of these in vitro data to the clinical setting confirms that the methylation status of the PLK2 CpG island predicts outcomes in patients treated with carboplatin and paclitaxel chemotherapy. A second cell cycle regulator, p57Kip2, is also subject to epigenetic silencing in carboplatin resistance in vitro and in vivo, emphasising that cell cycle regulators are important determinants of sensitivity to chemotherapeutic agents and providing insights into the phenomenon of collateral drug sensitivity in oncology. Understanding the mechanistic basis and identification of robust biomarkers to predict collateral sensitivity may inform optimal use of chemotherapy in patients receiving multiple lines of treatment

Dynamically-Coupled Oscillators -- Cooperative Behavior via Dynamical Interaction --

We propose a theoretical framework to study the cooperative behavior of dynamically coupled oscillators (DCOs) that possess dynamical interactions. Then, to understand synchronization phenomena in networks of interneurons which possess inhibitory interactions, we propose a DCO model with dynamics of interactions that tend to cause 180-degree phase lags. Employing an approach developed here, we demonstrate that although our model displays synchronization at high frequencies, it does not exhibit synchronization at low frequencies because this dynamical interaction does not cause a phase lag sufficiently large to cancel the effect of the inhibition. We interpret the disappearance of synchronization in our model with decreasing frequency as describing the breakdown of synchronization in the interneuron network of the CA1 area below the critical frequency of 20 Hz.Comment: 10 pages, 3 figure

A Millikelvin Scanned Probe for Measurement of Nanostructures

We demonstrate a scanning force microscope, based upon a quartz tuning fork, that operates below 100 mK and in magnetic fields up to 6 T. The microscope has a conducting tip for electrical probing of nanostructures of interest, and it incorporates a low noise cryogenic amplifier to measure both the vibrations of the tuning fork and the electrical signals from the nanostructures. At millikelvin temperatures the imaging resolution is below 1 um in a 22 um x 22 um range, and a coarse motion provides translations of a few mm. This scanned probe is useful for high bandwidth measurement of many high impedance nanostructures on a single sample. We show data locating an SET within an array and measure its coulomb blockade with a sensitivity of 2.6 x 10^-5 e/Hz^1/2.Comment: 5 pages, 5 figures, submitted to RS

Underuse of coronary revascularization procedures in patients considered appropriate candidates for revascularization.

Background: Ratings by an expert panel of the appropriateness of treatments may offer better guidance for clinical practice than the variable decisions of individual clinicians, yet there have been no prospective studies of clinical outcomes. We compared the clinical outcomes of patients treated medically after angiography with those of patients who underwent revascularization, within groups defined by ratings of the degree of appropriateness of revascularization in varying clinical circumstances.Methods: This was a prospective study of consecutive patients undergoing coronary angiography at three London hospitals. Before patients were recruited, a nine-member expert panel rated the appropriateness of percutaneous transluminal coronary angioplasty (PTCA) and coronary-artery bypass grafting (CABG) on a nine-point scale (with 1 denoting highly inappropriate and 9 denoting highly appropriate) for specific clinical indications. These ratings were then applied to a population of patients with coronary artery disease. However, the patients were treated without regard to the ratings. A total of 2552 patients were followed for a median of 30 months after angiography.Results: Of 908 patients with indications for which PTCA was rated appropriate (score, 7 to 9), 34 percent were treated medically; these patients were more likely to have angina at follow-up than those who underwent PTCA (odds ratio, 1.97; 95 percent confidence interval, 1.29 to 3.00). Of 1353 patients with indications for which CABG was considered appropriate, 26 percent were treated medically; they were more likely than those who underwent CABG to die or have a nonfatal myocardial infarction - the composite primary outcome (hazard ratio, 4.08; 95 percent confidence interval, 2.82 to 5.93) - and to have angina (odds ratio, 3.03; 95 percent confidence interval, 2.08 to 4.42). Furthermore, there was a graded relation between rating and outcome over the entire scale of appropriateness (P for linear trend = 0.002).Conclusions: On the basis of the ratings of the expert panel, we identified substantial underuse of coronary revascularization among patients who were considered appropriate candidates for these procedures. Underuse was associated with adverse clinical outcomes. (N Engl J Med 2001;344:645-54.) Copyright (C) 2001 Massachusetts Medical Society

Single electron charging of impurity sites visualized by scanning gate experiments on a quantum point contact

A quantum point contact (QPC) patterned on a two-dimensional electron gas is investigated with a scanning gate setup operated at a temperature of 300 mK. The conductance of the point contact is recorded while the local potential is modified by scanning the tip. Single electron charging of impurities induced by the local potential is observed as a stepwise conductance change of the constriction. By selectively changing the state of some of these impurities, it is possible to observe changes in transmission resonances of the QPC. The location of such impurities is determined, and their density is estimated to be below 50 per \mu m^2, corresponding to less than 1 % of the doping concentration

‘VIOLET’: a fluorescence-based simulation exercise for training healthcare workers in the use of personal protective equipment

Background Healthcare workers caring for patients with high-consequence infectious diseases (HCIDs) require protection from pathogen exposure, for example by wearing personal protective equipment (PPE). Protection is acquired through the inherent safety of the PPE components, but also their safe and correct use, supported by adequate training and user familiarity. However, the evidence base for HCID PPE ensembles and any associated training is lacking, with subsequent variation between healthcare providers. Aim To develop an evidence-based assessment and training tool for evaluating PPE ensembles and doffing protocols, in the assessment of patients with suspected HCIDs. Methods VIOLET (Visualising Infection with Optimised Light for Education and Training) comprises a healthcare mannequin adapted to deliver simulated bodily fluids containing UV-fluorescent tracers. On demand and remotely operated, the mannequin projectile vomits (blue), coughs (red), has diarrhoea (yellow) and is covered in sweat (orange). Wearing PPE, healthcare staff participate in an HCID risk assessment and examination of the ‘patient’, thereby becoming exposed to these bodily fluids. Contamination of PPE is visualized and body-mapped under UV light before and after removal. Observational findings and participant feedback, around its use as a training exercise, is also recorded. Findings Significant contamination from different exposure events was seen, enabling evaluation of PPE and doffing procedures used. Observational data and participant feedback demonstrated its strengths and success as a training technique. Conclusion Simulation exercises using VIOLET provide evidence-based assessment of PPE ensembles, and are a valuable resource for training of healthcare staff in wearing and safe doffing of PPE

Use of ultraviolet-fluorescence-based simulation in evaluation of personal protective equipment worn for first assessment and care of a patient with suspected high-consequence infectious disease

Background: Variations currently exist across the UK in the choice of personal protective equipment (PPE) used by healthcare workers when caring for patients with suspected high-consequence infectious diseases (HCIDs). Aim: To test the protection afforded to healthcare workers by current PPE ensembles during assessment of a suspected HCID case, and to provide an evidence base to justify proposal of a unified PPE ensemble for healthcare workers across the UK. Methods: One ‘basic level’ (enhanced precautions) PPE ensemble and five ‘suspected case’ PPE ensembles were evaluated in volunteer trials using ‘Violet’; an ultraviolet-fluorescence-based simulation exercise to visualize exposure/contamination events. Contamination was photographed and mapped. Findings: There were 147 post-simulation and 31 post-doffing contamination events, from a maximum of 980, when evaluating the basic level of PPE. Therefore, this PPE ensemble did not afford adequate protection, primarily due to direct contamination of exposed areas of the skin. For the five suspected case ensembles, 1584 post-simulation contamination events were recorded, from a maximum of 5110. Twelve post-doffing contamination events were also observed (face, two events; neck, one event; forearm, one event; lower legs, eight events). Conclusion: All suspected case PPE ensembles either had post-doffing contamination events or other significant disadvantages to their use. This identified the need to design a unified PPE ensemble and doffing procedure, incorporating the most protective PPE considered for each body area. This work has been presented to, and reviewed by, key stakeholders to decide on a proposed unified ensemble, subject to further evaluation