Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer

Background: Effective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy. Results: Breast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first–line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes. Conclusion: This study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer

Limits and dynamics of stochastic neuronal networks with random heterogeneous delays

Realistic networks display heterogeneous transmission delays. We analyze here the limits of large stochastic multi-populations networks with stochastic coupling and random interconnection delays. We show that depending on the nature of the delays distributions, a quenched or averaged propagation of chaos takes place in these networks, and that the network equations converge towards a delayed McKean-Vlasov equation with distributed delays. Our approach is mostly fitted to neuroscience applications. We instantiate in particular a classical neuronal model, the Wilson and Cowan system, and show that the obtained limit equations have Gaussian solutions whose mean and standard deviation satisfy a closed set of coupled delay differential equations in which the distribution of delays and the noise levels appear as parameters. This allows to uncover precisely the effects of noise, delays and coupling on the dynamics of such heterogeneous networks, in particular their role in the emergence of synchronized oscillations. We show in several examples that not only the averaged delay, but also the dispersion, govern the dynamics of such networks.Comment: Corrected misprint (useless stopping time) in proof of Lemma 1 and clarified a regularity hypothesis (remark 1

The dynamics of neural fields on bounded domains: an interface approach for Dirichlet boundary conditions

Continuum neural field equations model the large scale spatio-temporal dynamics of interacting neurons on a cortical surface. They have been extensively studied, both analytically and numerically, on bounded as well as unbounded domains. Neural field models do not require the specification of boundary conditions. Relatively little attention has been paid to the imposition of neural activity on the boundary, or to its role in inducing patterned states. Here we redress this imbalance by studying neural field models of Amari type (posed on one- and two-dimensional bounded domains) with Dirichlet boundary conditions. The Amari model has a Heaviside nonlinearity that allows for a description of localised solutions of the neural field with an interface dynamics. We show how to generalise this reduced but exact description by deriving a normal velocity rule for an interface that encapsulates boundary effects. The linear stability analysis of localised states in the interface dynamics is used to understand how spatially extended patterns may develop in the absence and presence of boundary conditions. Theoretical results for pattern formation are shown to be in excellent agreement with simulations of the full neural field model. Furthermore, a numerical scheme for the interface dynamics is introduced and used to probe the way in which a Dirichlet boundary condition can limit the growth of labyrinthine structures

Impact of a ward based clinical pharmacy service on drug-related hospital re-admissions - Evidence from a controlled clinical trial in a tertiary care hospital in Sri Lanka

Objective: To determine the impact of a ward-based clinical pharmacy service on drug related hospital re-admissions.Methods: This was a part of a controlled trial conducted in a tertiary care hospital in Sri Lanka to evaluate the clinical pharmacy service. The control group received the standard care whereas the intervention group received a ward-based pharmacist’s service in addition to the standard care. The pharmacist performed a prospective medications review of patients with chronic non-communicable diseases during their hospital stay and made recommendations to the health care team when appropriate. At discharge reconciliation of discharge prescription was done. Patients were educated about discharge medicines to improve knowledge and compliance. Both groups were followed up monthly for six months to identify drug-related hospital re-admissions.Results: Of 137 drug-related re-admissions, 93 (involving 87/356 patients) were from the control group, and 44 (involving 42/361 patients) were from the intervention group (P < 0.001). Non-compliance was the main reason for re-admissions in the control group and it was significantly higher in the control group (control vs. intervention: 53.8% vs. 34.1%; P = 0.013). Adverse drug reactions were the most common reason for re-admission in the intervention group (23/44; 52.3%). There was a significantly larger percentage of re-admissions in the control group due to unintentional omission of drugs on discharge prescription (control vs. intervention: 17.2% vs. 2.3%; P = 0.012).Conclusion: Ward based clinical pharmacy service was useful to reduce drug related hospital re-admissions in patients with chronic non-communicable diseases. Establishing a ward based clinical pharmacy service is recommended

Trends in UK cancer trials: results from the UK Coordinating Committee for Cancer Research National Register of Cancer Trials

We aimed to study trends in the design and conduct of randomised controlled trials (RCTs) in cancer in the UK, using the UK Coordinating Committee for Cancer Research (UKCCCR) National Register of Cancer Trials (NRCT). We conducted a descriptive survey of 520 UK RCTs in cancer that were registered on the UKCCCR NRCT. All trials had been initiated between 1971 and 2000. Trials on the NRCT have been conducted in a wide variety of cancer types, but with a third in breast (22%) or lung cancer (11%). They have largely been funded by the UK public and charity sectors. Overall, there has been a sustained rise in the total numbers of patients entering UK cancer trials over time with a trend towards larger, multicentre trials, greater recruitment targets and a marked reduction in the average time taken to complete trials. Trends in the design and conduct of noncommercial cancer RCTs from 1971 to 2000 are encouraging. It will be interesting to see how they develop in light of the implementation of recent national initiatives regarding cancer clinical trials in the UK

Synchrony-induced modes of oscillation of a neural field model

We investigate the modes of oscillation of heterogeneous ring-networks of quadratic integrate-and-fire (QIF) neurons with non-local, space-dependent coupling. Perturbations of the equilibrium state with a particular wave number produce transient standing waves with a specific temporal frequency, analogous to those in a tense string. In the neuronal network, the equilibrium corresponds to a spatially homogeneous, asynchronous state. Perturbations of this state excite the network’s oscillatory modes, which reflect the interplay of episodes of synchronous spiking with the excitatory-inhibitory spatial interactions. In the thermodynamic limit, an exact low-dimensional neural field model (QIF-NFM) describing the macroscopic dynamics of the network is derived. This allows us to obtain formulas for the Turing eigenvalues of the spatially-homogeneous state, and hence to obtain its stability boundary. We find that the frequency of each Turing mode depends on the corresponding Fourier coefficient of the synaptic pattern of connectivity. The decay rate instead, is identical for all oscillation modes as a consequence of the heterogeneity-induced desynchronization of the neurons. Finally, we numerically compute the spectrum of spatially-inhomogeneous solutions branching from the Turing bifurcation, showing that similar oscillatory modes operate in neural bump states, and are maintained away from onset

Thermodynamics of the bilinear-biquadratic spin one Heisenberg chain

The magnetic susceptibility and specific heat of the one-dimensional S=1 bilinear-biquadratic Heisenberg model are calculated using the transfer matrix renormalization group. By comparing the results with the experimental data of ${\rm LiVGe_2O_6}$ measured by Millet et al. (Phys. Rev. Lett. {\bf 83}, 4176 (1999)), we find that the susceptibility data of this material, after subtracting the impurity contribution, can be quantitatively explained with this model. The biquadratic exchange interaction in this material is found to be ferromagnetic, i.e. with a positive coupling constant.Comment: 4 pages, 4 postscript figure

Relationship between homocysteine and cardiorespiratory fitness is sex-dependent

Abstract Elevated plasma homocysteine is recognized as an independent risk factor for cardiovascular disease. Recently, there have been conflicting reports of the relationship between physical activity and homocysteine. A more objective measure of physical activity is cardiorespiratory fitness; however, its relationship with homocysteine has yet to be investigated. The aim of this study was to determine the relationship between cardiorespiratory fitness and plasma homocysteine. Cross-sectional associations between cardiorespiratory fitness (VO 2 max) and plasma homocysteine were examined in 49 men and 11 women. A submaximal bicycle test was used to determine VO 2 max and plasma homocysteine was measured using high performance liquid chromatography with fluorescence detection. Dietary analysis determined B vitamin intake. There was a significant inverse relationship between plasma homocysteine concentration and VO 2 max in women (r ϭ Ϫ0.81, P ϭ 0.003) but not in men (r ϭ Ϫ0.09, P ϭ 0.95). There were no significant relationships between plasma homocysteine and age, BMI, body fat, total cholesterol, and LDL cholesterol. In summary, elevated cardiorespiratory fitness is associated with decreased plasma homocysteine concentrations in women