Background: A major objective in the management of human papillomavirus (HPV)-positive squamous cell carcinoma of the head and neck (SCCHN) is to reduce long-term functional ramifications while ...maintaining oncological outcomes. This study examined the metabolic profile of HPV-positive SCCHN and the potential role of anti-metabolic therapeutics to achieve radiosensitisation as a potential means to de-escalate radiation therapy. Methods: Three established HPV-positive SCCHN cell lines were studied (UM-SCC-104, UPCI:SCC154, and VU-SCC-147), together with a typical TP53 mutant HPV-negative SCCHN cell line (UM-SCC-81B) for comparison. Metabolic profiling was performed using extracellular flux analysis during specifically designed mitochondrial and glycolytic stress tests. Sensitivity to ionising radiation (IR) was evaluated using clonogenic assays following no treatment, or treatment with: 25 mM 2-deoxy-D-glucose (glycolytic inhibitor) alone; 20 mM metformin (electron transport chain inhibitor) alone; or 25 mM 2-deoxy-D-glucose and 20 mM metformin combined. Expression levels of p53 and reporters of p53 function (MDM2, p53, Phospho-p53 Ser15, TIGAR and p21 CDKN1A) were examined by western blotting. Results: HPV-positive SCCHN cell lines exhibited a diverse metabolic phenotype, displaying robust mitochondrial and glycolytic reserve capacities. This metabolic profile, in turn, correlated with IR response following administration of anti-metabolic agents, in that both 2-deoxy-D-glucose and metformin were required to significantly potentiate the effects of IR in these cell lines. Conclusions: In contrast to our recently published data on HPV-negative SCCHN cells, which display relative glycolytic dependence, HPV-positive SCCHN cells can only be sensitised to IR using a complex anti-metabolic approach targeting both mitochondrial respiration and glycolysis, reflecting their metabolically diverse phenotype. Notionally, this may provide an attractive platform for treatment de-intensification in the clinical setting by facilitating IR dose reduction to minimise the impact of treatment on long-term function.
Introduction
Initiating disease-modifying treatments (DMTs) in multiple sclerosis (MS) is a major decision for people with (pw)MS but little is known about how the decision is perceived by the ...individual.
Objectives
The aim of the study was to determine if decisional conflict (DC) and decisional regret reflect different stages of the decision-making process when initiating DMTs.
Methods
This was a cross-sectional study of three cohorts of pwMS (n = 254), a ‘MS conference attendees’, ‘on treatment’ and an ‘offered treatment’ cohort. Questionnaires assessing DC, decisional regret and control preference were performed.
Results
Forty-four per cent (113/254) of pwMS were dissatisfied with their treatment status and 53% (135/254) had DC. DC (p = 0.013) and decisional regret (p = 0.027) increase in treatment-naïve pwMS and also in those ‘offered treatment’ dissatisfied with their treatment status (p < 0.0001), whilst those ‘on treatment’ have low Decisional Regret Scale (DRS) score (p = 0.0005). DC and DRS were only correlated with treatment status in those on treatment and not in treatment-naïve patients. Forty-three per cent (58/135) pwMS satisfied with treatment had DC. DC (n = 236, adjusted R2 0.137, p = 0.000) and DRS (n = 235, adjusted R2 0.232, p = 0.000) were increased by dissatisfaction with treatment, lower potency treatment, being from the ‘MS conference attendees’ cohort and reliance on the doctor’s decision, with DC additionally associated with being employed.
Conclusions
DC and decisional regret vary in populations at different stages of initiating DMTs and are impacted by non-treatment issues.
Abstract
In this paper, we revisit the Earnings, Cover (the ratio of earnings over dividends) and Price/Earnings (P/E) Ratio models which we introduced in Part 4 of this series. Although we suggested ...that the significant decline in the Earnings Index over 2015-2016 might be followed by dividends and share prices, this has not happened. Instead, Earnings have risen substantially over the years 2016 to 2018. Therefore, we revise our models based on the updated data and compare the new set of models with the one in Part 4 as well as with themselves. We then compare different methods for forecasting Dividends and Share Prices.
Process studies of E2212 (1) toward rapid clinical introduction are described. Through comprehensive route-finding studies and optimization of key condensation and cyclization steps, a racemate-based ...manufacturing route was established and successfully scaled-up to the hundred kilogram scale. For the rapid delivery of a drug substance containing the Z isomer for preclinical safety studies, the successful scale-up of the photoisomerization of an olefin in a flow system is also presented.
This is the third and last subpart of a long paper in which we consider stochastic interpolation for the Wilkie asset model, considering both Brownian bridges and Ornstein–Uhlenbeck (OU) bridges. In ...Part 3A, we developed certain properties for both these types of stochastic bridge, and in Part 3B we investigated retail prices and wages. In this paper, we investigate the remainder of many of our data series, relating to shares and interest rates. We conclude that, regardless of the form of the annual model, the monthly data within each year can be modelled by Brownian bridges, usually on the logarithm of the principal variable. But in no case is a simple Brownian bridge enough, and all series have their own peculiarities. Overall, however, our modelling produces simulations that are realistic in comparison with the known data. Many of our findings would apply to any similar model used for simulation over time. Our results have considerable importance for financial economics. We reconcile the conflict between the long-term mean-reverting modelling of Schiller and the short-term random walk modelling of Fama. This conclusion therefore has very wide significance.
Summary Objectives The precise role for intraventricular (IVT) antimicrobials in combination with systemic antibiotics in management of cerebrospinal fluid (CSF) diversion device-associated ...infections is uncertain. We evaluated our current practice, comparing dual therapy against systemic antimicrobials alone. Methods All adult patients with at least two consecutive CSF isolates who were treated for CSF diversion device-related infection over a 5-year period (2005–2010) were identified retrospectively. Clinical and laboratory parameters, microbiology, surgical and antimicrobial management, and treatment outcomes were analysed. Results Forty-eight patients were identified – 25 received IVT and systemic antibiotics (group A), and 23 systemic antibiotics alone (group B). Clinical features were similar between groups, as were causative organisms. CSF leucocyte counts differed slightly ( A > B , p = 0.067) but no laboratory parameters differed significantly. Infected devices were generally revised ( A = 92%, B = 91%). Mean times to CSF sterilisation and normalisation of CSF microscopy were significantly shorter for group A ( p < 0.05 and p < 0.005 respectively), as was duration of hospital stay ( p < 0.002) and required length of systemic antimicrobial therapy ( p < 0.001). Conclusions Our findings indicate that IVT antibiotics enhance clinical and microbiological recovery and should therefore be considered for patients with CSF infection associated with a CSF diversion device. We recommend further evaluation of this approach in a prospective, randomised, controlled trial.
This is the second subpart of three in a long paper in which we consider stochastic interpolation for the Wilkie asset model, considering both Brownian bridges and Ornstein–Uhlenbeck (OU) bridges. In ...Part 3A, we developed certain properties for both these types of stochastic bridge, and we investigate the properties of many of our data series on the same lines. We have several economic or investment series, which all have their own peculiarities. In this paper, we cover only retail prices and wages. The other series are dealt with in Part 3C. We find that, although the annual series for the rate of inflation is generated by an AR(1) model, which is the discrete time equivalent of an OU process, an OU bridge is not suitable. We need to use a Brownian bridge on the logarithm of the Price Index. Further, the standard deviation of the monthly increments in any year is, as we find empirically from the data, a function of the change in the annual value, and further there is correlation between the monthly increments in successive years.
In this paper, we develop certain properties for discrete Brownian bridges and Ornstein–Uhlenbeck bridges, which we use in the successor papers Part 3B and Part 3C to analyse real economic data ...series, with a view to constructing stochastic interpolation models for the Wilkie asset model.
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