Prognostic and predictive factors are indispensable tools in the treatment of patients with neoplastic disease. For the most part, such factors rely on a few specific cell surface, histological, or ...gross pathologic features. Gene expression assays have the potential to supplement what were previously a few distinct features with many thousands of features. We have developed Bayesian regression models that provide predictive capability based on gene expression data derived from DNA microarray analysis of a series of primary breast cancer samples. These patterns have the capacity to discriminate breast tumors on the basis of estrogen receptor status and also on the categorized lymph node status. Importantly, we assess the utility and validity of such models in predicting the status of tumors in crossvalidation determinations. The practical value of such approaches relies on the ability not only to assess relative probabilities of clinical outcomes for future samples but also to provide an honest assessment of the uncertainties associated with such predictive classifications on the basis of the selection of gene subsets for each validation analysis. This latter point is of critical importance in the ability to apply these methodologies to clinical assessment of tumor phenotype.
Treatment of the breast cancer cell line, MDAMB468 with the DNA methylation inhibitor, 5-azacytidine (5-AzaC) results in growth arrest, whereas the growth of the normal breast epithelial line DU99 ...(telomerase immortalized) is relatively unaffected. Comparing gene expression profiles of these two lines after 5-AzaC treatment, we identified 36 genes that had relatively low basal levels in MDAMB468 cells compared to the DU99 line and were induced in the cancer cell line but not in the normal breast epithelial line. Of these genes, 33 have associated CpG islands greater than 300 bp in length but only three have been previously described as targets for aberrant methylation in human cancer. Northern blotting for five of these genes (alpha-Catenin, DTR, FYN, GADD45a, and Zyxin) verified the array results. Further analysis of one of these genes, GADD45a, showed that 5-AzaC induced expression in five additional breast cancer cell lines with little or no induction in three additional lines derived from normal breast epithelial cells. The CpG island associated with GADD45a was analysed by bisulfite sequencing, sampling over 100 CpG dinucleotides. We found that four CpG's, located approximately 700 bp upstream of the transcriptional start site are methylated in the majority of breast cancer cell lines and primary tumors but not in DNA from normal breast epithelia or matched lymphocytes from cancer patients. Therefore, this simple method of dynamic transcriptional profiling yielded a series of novel methylation-sensitive genes in breast cancer including the BRCA1 and p53 responsive gene, GADD45a.
The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of ...cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.
Screening programs using retinal photography for the detection of diabetic eye disease are being introduced in the U.K. and elsewhere. Automatic grading of the images is being considered by health ...boards so that the human grading task is reduced. Microaneurysms (MAs) are the earliest sign of this disease and so are very important for classifying whether images show signs of retinopathy. This paper describes automatic methods for MA detection and shows how image contrast normalization can improve the ability to distinguish between MAs and other dots that occur on the retina. Various methods for contrast normalization are compared. Best results were obtained with a method that uses the watershed transform to derive a region that contains no vessels or other lesions. Dots within vessels are handled successfully using a local vessel detection technique. Results are presented for detection of individual MAs and for detection of images containing MAs. Images containing MAs are detected with sensitivity 85.4% and specificity 83.1%
Single equimolar doses (0.5 micromoles/kg body wt) of lutein and/or beta-carotene in true solution in oil were given to eight adult subjects and 13 blood samples were taken during the subsequent 840 ...h. Whereas the mean serum concentration of lutein showed a single maximum at 16 h, that of beta-carotene peaked at 6 h and then again at 32 h. Subsequently, lutein and beta-carotene were cleared at approximately the same rate from the serum. The mean (+/-SEM) areas under the curve (AUCs) for lutein and beta-carotene during the first 440 h differed significantly: 59.6 +/- 9.0 and 26.3 +/- 6.4 micromoles. h/L, respectively (P 0.005). AUC values did not correlate with initial serum concentrations of the given carotenoid or with the order of dosing. When combined in the same dose, beta-carotene significantly reduced the serum AUC values for lutein to 54-61% of control values (P 0.025), whereas lutein reduced the AUC value for beta-carotene in five subjects but enhanced it in three subjects. Effects of lutein on the AUC for beta-carotene were inversely related to the AUC for beta-carotene alone. Thus, carotenoids clearly interact with each other during intestinal absorption, metabolism, and serum clearance, although individual responses can differ markedly
Aims
To assess the cost‐effectiveness of adopting risk‐stratified approaches to extended screening intervals in the national diabetic retinopathy screening programme in Scotland.
Methods
A ...continuous‐time hidden Markov model was fitted to national longitudinal screening data to derive transition probabilities between observed non‐referable and referable retinopathy states. These were incorporated in a decision model simulating progression, costs and visual acuity outcomes for a synthetic cohort with a covariate distribution matching that of the Scottish diabetic screening population. The cost‐effectiveness of adopting extended (2–year) screening for groups with no observed retinopathy was then assessed over a 30–year time horizon.
Results
Individuals with a current grade of no retinopathy on two consecutive screening episodes face the lowest risk of progressing to referable disease. For the cohort as a whole, the incremental cost per quality‐adjusted life year gained for annual vs. biennial screening ranged from approximately £74 000 (for those with no retinopathy and a prior observed grade of mild or observable background retinopathy) to approximately £232 000 per quality‐adjusted life year gained (for those with no retinopathy on two consecutive screening episodes). The corresponding incremental cost‐effectiveness ratios in the subgroup with Type 1 diabetes were substantially lower; approximately £22 000 to £85 000 per quality‐adjusted life year gained, respectively.
Conclusions
Biennial screening for individuals with diabetes who have no retinopathy is likely to deliver significant savings for a very small increase in the risk of adverse visual acuity and quality of life outcomes. There is greater uncertainty regarding the long‐term cost‐effectiveness of adopting biennial screening in younger people with Type 1 diabetes.
What's new?
A microsimulation model of the diabetic retinopathy screening and treatment pathways in Scotland was developed; incorporating risks of progression estimated from contemporary, longitudinal, population‐based screening outcome data.
The adoption of biennial screening intervals for those with diabetes and no diabetic retinopathy is likely to be cost‐effective.
There is greater uncertainty surrounding the long‐term cost‐effectiveness of biennial screening in younger people with Type 1 diabetes and no retinopathy, due to the higher long‐term cumulative risk of developing interval referable disease, and a lower competing risk of death from all causes.
To evaluate the performance of an automated retinal image quality assessment system for use in automated diabetic retinopathy grading.
Algorithmic methods have been developed for assessing the ...quality of 45 degrees single field retinal images for use in diabetic retinopathy screening. For this purpose, image quality was defined by two aspects: image clarity and field definition. An image with adequate clarity was defined as one that shows sufficient detail for automated retinopathy grading. The visibility of the macular vessels was used as an indicator of image clarity, since these vessels are known to be narrow and become less visible with any image degradation. An image with adequate field definition was defined as one that shows the desired field of view for retinopathy grading, including the full 45 degrees field of view, the optic disc, and at least two optic disc diameters of visible retina around the fovea. From 489 patients attending a diabetic retinopathy screening program, 1039 retinal images were obtained. The images were graded by a clinician for image clarity and field definition, with a comprehensive image-quality grading scheme.
The sensitivity and specificity were, respectively, 100% and 90.9% for inadequate clarity detection, 95.3% and 96.4% for inadequate field definition detection, and 99.1% and 89.4% for inadequate overall quality detection.
The automated system performs with sufficient accuracy to form part of an automated diabetic retinopathy grading system.
Lack of benefit and potential harm of early parenteral nutrition (PN) initiation in critically ill children was highlighted in the 2016 published results of a large multicenter, randomized controlled ...trial.
The purpose of this project was to implement a process to delay PN initiation for up to five days after admission to our pediatric intensive care unit (PICU).
Patients greater than thirty days of age, admitted to the PICU beginning July 1, 2016 were included in the analysis of the healthcare improvement initiative to decrease early PN initiation. A meeting was held with PICU fellows, attending physicians, dietitians, and pharmacists to reach a consensus to delay initiation of parenteral nutrition until PICU day five. The dietitian, with pharmacist support, reiterated recommendations on rounds and in formal notes.
A total of 2333 patients were identified in the pre-intervention group and a total of 2491 patients in the post-intervention group. The percentage of patients receiving PN prior to day five within the PICU was 5.5% in the pre-intervention group versus 3.1% in the delayed PN group (p<0.001). PICU patients receiving PN less than or equal to three days decreased from 2.6% pre-intervention to 1.5% post-intervention (p=0.01). For the subset of patients who were initiated on PN after admission to the PICU, median PICU length of stay was 7 days versus 6 days in the pre-intervention versus post-intervention group (p=0.26).
Decrease in PN utilization was seen in the pre and post-intervention groups as assessed by percentage of patients initiated on PN prior to day five of PICU admission. Consensus among practitioners with consistent recommendations from the frontline dietitian and pharmacist, with nutrition support team collaboration, contributed to the evidence based quality initiative results. Delaying PN did not adversely affect length of stay pre versus post-intervention.
A model is presented to predict the orientation and concentration state of a semi-dilute, rigid fibre suspension in a plane channel flow. A probability distribution function is used to describe the ...local orientation and concentration states of the suspension and evolves according to a Fokker–Planck equation. The fibres are free to interact with each other hydrodynamically and are modelled using the approach outlined by Folgar & Tucker (J. Reinf. Plast. Comp. vol. 3, 1984, p. 98). Near the channel walls, the no-flux boundary conditions as proposed by Schiek & Shaqfeh (J. Fluid Mech. vol. 296, 1995, p. 271) are applied on the orientation distribution function. With this approach, geometric constraints are used to couple the fibres' rotary motion with their translational motion. This eliminates physically unrealistic orientation states in the near-wall region. The concentration distribution is modelled in a similar manner to that proposed by Ma & Graham (Phys. Fluids vol. 17, 2005, art. 083103). A two-way coupling between the fibre orientation state and the momentum equations of the suspending fluid is considered. Experiments are performed to validate the numerical model by visualizing the motion of tracer fibres in an index-of-refraction matched suspension. The orientation distribution function is determined experimentally based on these observations of fibre motion and a comparison is made with the model predictions. Good agreement is shown particularly near the channel walls. The results indicate that at distances less than one-half of a fibre length from the channel walls, the model accurately predicts the available fibre orientation states and the distribution of fibres amongst these states. The model further predicts a large concentration gradient in this region that is also observed experimentally. The magnitude of the concentration gradient in the near-wall region is shown to increase with increasing fibre concentration.
Indolo2,1-bquinazoline-6,12-dione (tryptanthrin) was imaged at the solution-graphite interface using scanning tunneling microscopy. STM images of the molecular monolayers show clear lobe-to-lobe ...resolution of the lowest unoccupied molecular orbitals of the molecules, as well as a somewhat unusual parallel arrangement of the molecular dipoles. Evaluation of the dipole-dipole interactions reveals that the interactions of the closest molecule pairs are reduced due to a magic angle-like effect. These results represent an important step toward a more in-depth understanding of the behavior of tryptanthrins, which are of interest due to their potential as pharmaceutical compounds.
•We have achieved sub‐molecular resolution of tryptanthrin using STM.•The molecule image corresponds directly to the calculated LUMO.•The surface molecules display very unusual parallel dipole alignment.•The electrostatic interactions of the dipoles are described.•These results are important for continued STM studies of tryptanthrin as a potential anti‐malarial agent.
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