Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma

Neoadjuvant chemoradiation therapy (CRT) is increasingly the standard of care for locally advanced oesophageal cancer. A complete pathological response to CRT is associated with a favourable outcome. Radiation therapy is important for local tumour control, however, radioresistance remains a substantial clinical problem. We hypothesise that alterations in mitochondrial function and energy metabolism are involved in the radioresistance of oesophageal adenocarcinoma (OAC). To investigate this, we used an established isogenic cell line model of radioresistant OAC. Radioresistant cells (OE33 R) demonstrated significantly increased levels of random mitochondrial mutations, which were coupled with alterations in mitochondrial function, size, morphology and gene expression, supporting a role for mitochondrial dysfunction in the radioresistance of this model. OE33 R cells also demonstrated altered bioenergetics, demonstrating significantly increased intracellular ATP levels, which was attributed to enhanced mitochondrial respiration. Radioresistant cells also demonstrated metabolic plasticity, efficiently switching between the glycolysis and oxidative phosphorylation energy metabolism pathways, which were accompanied by enhanced clonogenic survival. This data was supported in vivo, in pre-treatment OAC tumour tissue. Tumour ATP5B expression, a marker of oxidative phosphorylation, was significantly increased in patients who subsequently had a poor pathological response to neoadjuvant CRT. This suggests for the first time, a role for specific mitochondrial alterations and metabolic remodelling in the radioresistance of OAC

Monotonic properties of the shift and penetration factors

We study derivatives of the shift and penetration factors of collision theory with respect to energy, angular momentum, and charge. Definitive results for the signs of these derivatives are found for the repulsive Coulomb case. In particular, we find that the derivative of the shift factor with respect to energy is positive for the repulsive Coulomb case, a long anticipated but heretofore unproven result. These results are closely connected to the properties of the sum of squares of the regular and irregular Coulomb functions; we also present investigations of this quantity.Comment: 13 pages, 1 figur

Aspergillus nodules; another presentation of Chronic Pulmonary Aspergillosis

BACKGROUND: There are a number of different manifestations of pulmonary aspergillosis. This study aims to review the radiology, presentation, and histological features of lung nodules caused by Aspergillus spp. METHODS: Patients were identified from a cohort attending our specialist Chronic Pulmonary Aspergillosis clinic. Patients with cavitating lung lesions, with or without fibrosis and those with aspergillomas or a diagnosis of invasive aspergillosis were excluded. Demographic, laboratory, and clinical data and radiologic findings were recorded. RESULTS: Thirty-three patients with pulmonary nodules and diagnostic features of aspergillosis (histology and/or laboratory findings) were identified. Eighteen (54.5 %) were male, mean age 58 years (range 27–80 years). 19 (57.6 %) were former or current smokers. The median Charleston co-morbidity index was 3 (range 0–7). All complained of a least one of; dyspnoea, cough, haemoptysis, or weight loss. None reported fever. Ten patients (31 %) did not have an elevated Aspergillus IgG, and only 4 patients had elevated Aspergillus precipitins. Twelve patients (36 %) had a single nodule, six patients (18 %) had between 2 and 5 nodules, 2 (6 %) between 6 and 10 nodules and 13 (39 %) had more than 10 nodules. The mean size of the nodules was 21 mm, with a maximum size ranging between 5–50 mm. No nodules had cavitation radiographically. The upper lobes were most commonly involved. Histology was available for 18 patients and showed evidence of granulation tissue, fibrosis, and visualisation of fungal hyphae. CONCLUSION: Pulmonary nodules are a less common manifestation of aspergillosis in immunocompetent patients. Distinguishing these nodules from other lung pathology may be difficult on CT findings alone

Mining Explainable Predictive Features for Water Quality Management

With water quality management processes, identifying and interpreting relationships between features, such as location and weather variable tuples, and water quality variables, such as levels of bacteria, is key to gaining insights and identifying areas where interventions should be made. There is a need for a search process to identify the locations and types of phenomena that are influencing water quality and a need to explain how the quality is being affected and which factors are most relevant. This paper addresses both of these issues. A process is developed for collecting data for features that represent a variety of variables over a spatial region and which are used for training models and inference. An analysis of the performance of the features is undertaken using the models and Shapley values. Shapley values originated in cooperative game theory and can be used to aid in the interpretation of machine learning results. Evaluations are performed using several machine learning algorithms and water quality data from the Dublin Grand Canal basin

Population Dynamics of Sugar Beets, \u3ci\u3eRhizoctonia solani\u3c/i\u3e, and \u3ci\u3eLaetisaria arvalis\u3c/i\u3e: Responses of a Host, Plant Pathogen, and Hyperparasite to Perturbation in the Field

Rhizoctonia solani causes crown rot of sugar beets, a severe disease that has destroyed up to 60% of the plants in a test field in western Nebraska. Laetisaria arvalis, a natural hyperparasite of Rhizoctonia spp., was isolated from fields in western Nebraska. To test for the potential for biological control of R. solani, in November 1980 (following harvest) we applied various combinations of a nematicide (Telone II; Dow Chemical Co.), a nutrition source (sugar beet pulp), and an inoculum of L. arvalis in a randomized block design. Populations of R. solani, L. arvalis, and sugar beets were monitored monthly through October 1981 (just after harvest). In control and nematicide plots, the R. solani population did not change significantly through time. In plots inoculated with L. arvalis, the R. solani populations declined through March, concomitant with an increase in L. arvalis. L. arvalis then declined with a corresponding increase in the R. solani populations. Beet plant numbers declined significantly in all treatments. We suggest that reduction of the R. solani populations with the hyperparasite L. arvalis is possible but that a stable equilibrium naturally exists

Effects of Methylene Blue and Polyethelene Glycol on Facial Nerve Axotomy Recovery

poster abstractInjury and disease are common factors affecting peripheral nerves and can lead to loss of function. Recovery time after an injury is slow and not very efficient in humans. Treatment methods involving methylene blue (MB) and polyethylene glycol (PEG) have shown combinational effects in sciatic nerve axotomies. We are using behavior analysis of eye blink reflex and vibrissae orientation and movement as a measurement of rate of functional recovery. We will have treatment groups of both cut and crush rats. For each group we will be testing the effect of PEG/MB or no treatment control groups. The results of these treatment groups are significant to finding treatment options for clinical use

Application of a single-objective, hybrid genetic algorithm approach to pharmacokinetic model building.

A limitation in traditional stepwise population pharmacokinetic model building is the difficulty in handling interactions between model components. To address this issue, a method was previously introduced which couples NONMEM parameter estimation and model fitness evaluation to a single-objective, hybrid genetic algorithm for global optimization of the model structure. In this study, the generalizability of this approach for pharmacokinetic model building is evaluated by comparing (1) correct and spurious covariate relationships in a simulated dataset resulting from automated stepwise covariate modeling, Lasso methods, and single-objective hybrid genetic algorithm approaches to covariate identification and (2) information criteria values, model structures, convergence, and model parameter values resulting from manual stepwise versus single-objective, hybrid genetic algorithm approaches to model building for seven compounds. Both manual stepwise and single-objective, hybrid genetic algorithm approaches to model building were applied, blinded to the results of the other approach, for selection of the compartment structure as well as inclusion and model form of inter-individual and inter-occasion variability, residual error, and covariates from a common set of model options. For the simulated dataset, stepwise covariate modeling identified three of four true covariates and two spurious covariates; Lasso identified two of four true and 0 spurious covariates; and the single-objective, hybrid genetic algorithm identified three of four true covariates and one spurious covariate. For the clinical datasets, the Akaike information criterion was a median of 22.3 points lower (range of 470.5 point decrease to 0.1 point decrease) for the best single-objective hybrid genetic-algorithm candidate model versus the final manual stepwise model: the Akaike information criterion was lower by greater than 10 points for four compounds and differed by less than 10 points for three compounds. The root mean squared error and absolute mean prediction error of the best single-objective hybrid genetic algorithm candidates were a median of 0.2 points higher (range of 38.9 point decrease to 27.3 point increase) and 0.02 points lower (range of 0.98 point decrease to 0.74 point increase), respectively, than that of the final stepwise models. In addition, the best single-objective, hybrid genetic algorithm candidate models had successful convergence and covariance steps for each compound, used the same compartment structure as the manual stepwise approach for 6 of 7 (86 %) compounds, and identified 54 % (7 of 13) of covariates included by the manual stepwise approach and 16 covariate relationships not included by manual stepwise models. The model parameter values between the final manual stepwise and best single-objective, hybrid genetic algorithm models differed by a median of 26.7 % (q₁ = 4.9 % and q₃ = 57.1 %). Finally, the single-objective, hybrid genetic algorithm approach was able to identify models capable of estimating absorption rate parameters for four compounds that the manual stepwise approach did not identify. The single-objective, hybrid genetic algorithm represents a general pharmacokinetic model building methodology whose ability to rapidly search the feasible solution space leads to nearly equivalent or superior model fits to pharmacokinetic data

Trait positive and negative emotionality differentially associate withdiurnal cortisol activity

Inter-individual variability in metrics of hypothalamic-pituitary-adrenocortical (HPA) activity, such asthe slope of the diurnal decline in cortisol, cortisol awakening response (CAR), and total cortisol out-put, have been found to associate inversely with trait ratings of extraversion and positive affect (E/PA)and positively with neuroticism and negative affect (N/NA) in some, but not all, investigations. Theseinconsistencies may partly reflect varied intensity of cortisol sampling among studies and reliance onself-rated traits, which are subject to reporting biases and limitations of introspection. Here, we furtherexamined dispositional correlates of HPA activity in 490 healthy, employed midlife volunteers (M age = 43years; 54% Female; 86% white). Trait ratings were requested from participants and 2 participant-electedinformants using the Positive and Negative Affect Schedule (PANAS) and Extraversion and Neuroticismdimensions of NEO personality inventories. CAR was assessed as percent increase in cortisol levels fromawakening to 30 min after awakening; and the diurnal slope and total output of cortisol [Area Underthe Curve (AUC)] were determined from cortisol measurements taken at awakening, +4 and +9 h later,and bedtime, across 3 workdays. Structural equation modeling was used to estimate multi-informantE/PA and N/NA factors. We used 3 days of measurement as indicators to model each of the three latentcortisol factors (slope, CAR, and AUC). With the two latent emotionality and three latent cortisol indicesincluded there was good fit to the data ( 2(200)= 278.38, p = 0.0002; RMSEA = 0.028, 90% CI = 0.02–0.04;CFI/TLI = 0.97/0.96; SRMR = 0.04). After controlling for covariates (age, sex, race), results showed higherlatent E/PA associated with a steeper diurnal slope (Standardized ˇ = −0.19, p = 0.02) and smaller CAR(Standardized ˇ = −0.26, p = 0.004), whereas N/NA did not associate with any cortisol metric (Standard-ized ˇ’s = −0.12 to 0.13, p’s = 0.10 to 0.53). These findings suggest that positive emotionality may be moreclosely associated with indices of diurnal cortisol release than negative emotionality

Measuring health-related quality of life in chronic headache: A comparative evaluation of the Chronic Headache Quality of Life Questionnaire and Headache Impact Test (HIT-6).

OBJECTIVE: To compare the quality and acceptability of a new headache-specific patient-reported measure, the Chronic Headache Quality of Life Questionnaire (CHQLQ) with the six-item Headache Impact Test (HIT-6), in people meeting an epidemiological definition of chronic headaches. METHODS: Participants in the feasibility stage of the Chronic Headache Education and Self-management Study (CHESS) (n = 130) completed measures three times during a 12-week prospective cohort study. Data quality, measurement acceptability, reliability, validity, responsiveness to change, and score interpretation were determined. Semi-structured cognitive interviews explored measurement relevance, acceptability, clarity, and comprehensiveness. RESULTS: Both measures were well completed with few missing items. The CHQLQ's inclusion of emotional wellbeing items increased its relevance to participant's experience of chronic headache. End effects were present at item level only for both measures. Structural assessment supported the three and one-factor solutions of the CHQLQ and HIT-6, respectively. Both the CHQLQ (range 0.87 to 0.94) and HIT-6 (0.90) were internally consistent, with acceptable temporal stability over 2 weeks (CHQLQ range 0.74 to 0.80; HIT-6 0.86). Both measures responded to change in headache-specific health at 12 weeks (CHQLQ smallest detectable change (improvement) range 3 to 5; HIT-6 2.1). CONCLUSIONS: While both measures are structurally valid, internally consistent, temporally stable, and responsive to change, the CHQLQ has greater relevance to the patient experience of chronic headache.Trial registration number: ISRCTN79708100. Registered 16th December 2015, http://www.isrctn.com/ISRCTN79708100