Localisation of heat shock proteins in haematological malignancies

Although a number of HSPs have been shown to be up-regulated in a wide range of human cancers, the full significance of this remains to be determined. The localisation of HSPs seems to be critical in determining their role in cancer cell survival; High intracellular levels (iHsp) appear to be advantageous to the tumour cell, inhibiting key steps in apoptosis, while in some circumstances, surface expression (sHsp) appears to be detrimental to the cell, aiding immune recognition by various effector cells. Consequently, clarifying the importance of HSP cellular location in the cancer setting may lead to the development of novel therapies based upon manipulation of HSP localisation. This thesis had two major aims; (1) to investigate the cellular localisation of HSPs in leukocytes from patients with both myelocytic and lymphocytic malignancies in order to establish relationships between apoptosis and stage of disease (2) to study the synergistic effect of four chemotherapeutic drugs with membrane fluidising agents, compounds which have the potential to modulate HSP localisation. Hsp90 and Hsp27 expression was shown to be restricted to the inside of peripheral blood leukocytes, while Hsp72 was localised both intracellularly and on the cell surface. In CLL, iHsp90 and iHsp27 levels were found to be significantly higher than in control subjects, while surface and intracellular Hsp72 was shown to be expressed either at very high levels or at very low levels. Furthermore, iHsp90 levels were found to be associated with stage of disease, while iHsp27 levels were shown to negatively correlate with levels of apoptosis. CLL patients with stable disease were found to express higher levels of iHsp72 than patients with progressive disease. However, in AML and MDS, levels of all HSPs in peripheral blood were found to be similar to those seen in control subjects, but disease patients showed a much wider range of expression. In AML, levels of sHsp72 positively correlated in all cell types, an observation not made in MDS patients or control subjects. HSP localisation was shown to be affected by membrane fluidising agents, with a movement of Hsp72 and Hsp60 to the cell surface. This effect was not due to proteotoxicity and supports data implicating the cell membrane in the regulation of HSP responses. This manipulation of HSP localisation and the increase in membrane fluidity resulted in increased sensitivity of CLL cells to three chemotherapeutic agents and points to the possibility that manipulation of membrane fluidity, may have significant value in the development of new treatment regimes

Evaluating the Possibility of Translating Technological Advances in Non-Invasive Continuous Lactate Monitoring into Critical Care.

Lactate is widely measured in critically ill patients as a robust indicator of patient deterioration and response to treatment. Plasma concentrations represent a balance between lactate production and clearance. Analysis has typically been performed with the aim of detecting tissue hypoxia. However, there is a diverse range of processes unrelated to increased anaerobic metabolism that result in the accumulation of lactate, complicating clinical interpretation. Further, lactate levels can change rapidly over short spaces of time, and even subtle changes can reflect a profound change in the patient’s condition. Hence, there is a significant need for frequent lactate monitoring in critical care. Lactate monitoring is commonplace in sports performance monitoring, given the elevation of lactate during anaerobic exercise. The desire to continuously monitor lactate in athletes has led to the development of various technological approaches for non-invasive, continuous lactate measurements. This review aims firstly to reflect on the potential benefits of non-invasive continuous monitoring technology within the critical care setting. Secondly, we review the current devices used to measure lactate non-invasively outside of this setting and consider the challenges that must be overcome to allow for the translation of this technology into intensive care medicine. This review will be of interest to those developing continuous monitoring sensors, opening up a new field of research

Evaluating the Possibility of Translating Technological Advances in Non-Invasive Continuous Lactate Monitoring into Critical Care

Lactate is widely measured in critically ill patients as a robust indicator of patient deterioration and response to treatment. Plasma concentrations represent a balance between lactate production and clearance. Analysis has typically been performed with the aim of detecting tissue hypoxia. However, there is a diverse range of processes unrelated to increased anaerobic metabolism that result in the accumulation of lactate, complicating clinical interpretation. Further, lactate levels can change rapidly over short spaces of time, and even subtle changes can reflect a profound change in the patient’s condition. Hence, there is a significant need for frequent lactate monitoring in critical care. Lactate monitoring is commonplace in sports performance monitoring, given the elevation of lactate during anaerobic exercise. The desire to continuously monitor lactate in athletes has led to the development of various technological approaches for non-invasive, continuous lactate measurements. This review aims firstly to reflect on the potential benefits of non-invasive continuous monitoring technology within the critical care setting. Secondly, we review the current devices used to measure lactate non-invasively outside of this setting and consider the challenges that must be overcome to allow for the translation of this technology into intensive care medicine. This review will be of interest to those developing continuous monitoring sensors, opening up a new field of research

Molecularly imprinted polymer based electrochemical biosensors: Overcoming the challenges of detecting vital biomarkers and speeding up diagnosis

Electrochemical biosensors for the detection of vital biomarkers is a well-established technology that utilises a transducer and recognition element in tandem to determine the presence of an analyte. There is growing interest in using Molecularly Imprinted Polymers (MIPs) as recognition elements in a wide range of sensing devices due to their economic viability and scalability. The inherent properties of polymer platforms, alongside the vast array of monomeric options, synthetic routes and incorporation strategies allow for the production of a multitude of sensitive and selective recognition elements that have significant advantages over classically utilised biological entities. MIPs exhibit superior chemical and thermal stability offering a wider variety of immobilization/incorporation strategies, virtually unlimited ambient shelf-life and a longer product lifetime, whilst the vast array of monomers available offer flexibility to their synthesis. Even though some sensor platforms have been reported for the detection of vital biomarkers, the use of MIPs has a number of challenges and drawbacks that need to be overcome in order to produce sensing platforms with the required sensitivity and specificity for clinical use. In this review, we will provide an overview of the reasoning behind using MIPs as recognition elements in electrochemical biosensors for vital biomarkers, discuss the problems synergizing MIPs and electrochemical read-out strategies and offer insights into the future perspectives of this promising and innovative technology

Acute effects of breaking up prolonged sitting on fatigue and cognition: a pilot study.

OBJECTIVES: To compare the acute effects of uninterrupted sitting with sitting interrupted by brief bouts of light-intensity walking on self-reported fatigue, cognition, neuroendocrine biomarkers and cardiometabolic risk markers in overweight/obese adults. DESIGN: Randomised two-condition crossover trial. SETTING: Laboratory study conducted in Melbourne, Australia. PARTICIPANTS: 19 overweight/obese adults (45-75 years). INTERVENTIONS: After an initial 2 h period seated, participants consumed a meal-replacement beverage and completed (on 2 days separated by a 6-day washout period) each condition over the next 5 h: uninterrupted sitting (sedentary condition) or sitting with 3 min bouts of light-intensity walking every 30 min (active condition). PRIMARY OUTCOME MEASURES: Self-reported fatigue, executive function and episodic memory at 0 h, 4 h and 7 h. SECONDARY OUTCOME MEASURES: Neuroendocrine biomarkers and cardiometabolic risk markers (blood collections at 0 h, 4 h and 7 h, blood pressure and heart rate measured hourly and interstitial glucose measured using a continuous glucose monitoring system). RESULTS: During the active condition, fatigue levels were lower at 4 h (-13.32 (95% CI -23.48 to -3.16)) and at 7 h (-10.73 (95% CI -20.89 to -0.58)) compared to the sedentary condition. Heart rate was higher at 4 h (4.47 (95% CI 8.37 to 0.58)) and at 7 h (4.32 (95% CI 8.21 to 0.42)) during the active condition compared to the sedentary condition. There were no significant differences between conditions by time for other variables. In the sedentary condition, changes in fatigue scores over time correlated with a decrease in heart rate and plasma dihydroxyphenylalanine (DOPA) and an increase in plasma dihydroxyphenylglycol (DHPG). CONCLUSIONS: Interrupting prolonged sitting with light-intensity walking breaks may be an effective fatigue countermeasure acutely. Fatigue levels corresponded with the heart rate and neuroendocrine biomarker changes in uninterrupted sitting in this pilot study. Further research is needed to identify potential implications, particularly for the occupational health context. TRIAL REGISTRATION NUMBER: ACTRN12613000137796; Results

Modular Synthesis and Biological Investigation of 5-Hydroxymethyl Dibenzyl Butyrolactones and Related Lignans

Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway

The role of ETG modes in JET-ILW pedestals with varying levels of power and fuelling

We present the results of GENE gyrokinetic calculations based on a series of JET-ITER-like-wall (ILW) type I ELMy H-mode discharges operating with similar experimental inputs but at different levels of power and gas fuelling. We show that turbulence due to electron-temperature-gradient (ETGs) modes produces a significant amount of heat flux in four JET-ILW discharges, and, when combined with neoclassical simulations, is able to reproduce the experimental heat flux for the two low gas pulses. The simulations plausibly reproduce the high-gas heat fluxes as well, although power balance analysis is complicated by short ELM cycles. By independently varying the normalised temperature gradients (omega(T)(e)) and normalised density gradients (omega(ne )) around their experimental values, we demonstrate that it is the ratio of these two quantities eta(e) = omega(Te)/omega(ne) that determines the location of the peak in the ETG growth rate and heat flux spectra. The heat flux increases rapidly as eta(e) increases above the experimental point, suggesting that ETGs limit the temperature gradient in these pulses. When quantities are normalised using the minor radius, only increases in omega(Te) produce appreciable increases in the ETG growth rates, as well as the largest increases in turbulent heat flux which follow scalings similar to that of critical balance theory. However, when the heat flux is normalised to the electron gyro-Bohm heat flux using the temperature gradient scale length L-Te, it follows a linear trend in correspondence with previous work by different authors

Interpretative and predictive modelling of Joint European Torus collisionality scans

Transport modelling of Joint European Torus (JET) dimensionless collisionality scaling experiments in various operational scenarios is presented. Interpretative simulations at a fixed radial position are combined with predictive JETTO simulations of temperatures and densities, using the TGLF transport model. The model includes electromagnetic effects and collisions as well as □(→┬E ) X □(→┬B ) shear in Miller geometry. Focus is on particle transport and the role of the neutral beam injection (NBI) particle source for the density peaking. The experimental 3-point collisionality scans include L-mode, and H-mode (D and H and higher beta D plasma) plasmas in a total of 12 discharges. Experimental results presented in (Tala et al 2017 44th EPS Conf.) indicate that for the H-mode scans, the NBI particle source plays an important role for the density peaking, whereas for the L-mode scan, the influence of the particle source is small. In general, both the interpretative and predictive transport simulations support the experimental conclusions on the role of the NBI particle source for the 12 JET discharges

Shattered pellet injection experiments at JET in support of the ITER disruption mitigation system design

A series of experiments have been executed at JET to assess the efficacy of the newly installed shattered pellet injection (SPI) system in mitigating the effects of disruptions. Issues, important for the ITER disruption mitigation system, such as thermal load mitigation, avoidance of runaway electron (RE) formation, radiation asymmetries during thermal quench mitigation, electromagnetic load control and RE energy dissipation have been addressed over a large parameter range. The efficiency of the mitigation has been examined for the various SPI injection strategies. The paper summarises the results from these JET SPI experiments and discusses their implications for the ITER disruption mitigation scheme