Immunosignaturing can detect products from molecular markers in brain cancer.

Immunosignaturing shows promise as a general approach to diagnosis. It has been shown to detect immunological signs of infection early during the course of disease and to distinguish Alzheimer's disease from healthy controls. Here we test whether immunosignatures correspond to clinical classifications of disease using samples from people with brain tumors. Blood samples from patients undergoing craniotomies for therapeutically naïve brain tumors with diagnoses of astrocytoma (23 samples), Glioblastoma multiforme (22 samples), mixed oligodendroglioma/astrocytoma (16 samples), oligodendroglioma (18 samples), and 34 otherwise healthy controls were tested by immunosignature. Because samples were taken prior to adjuvant therapy, they are unlikely to be perturbed by non-cancer related affects. The immunosignaturing platform distinguished not only brain cancer from controls, but also pathologically important features about the tumor including type, grade, and the presence or absence of O(6)-methyl-guanine-DNA methyltransferase methylation promoter (MGMT), an important biomarker that predicts response to temozolomide in Glioblastoma multiformae patients

Classification of multiple cancer types and molecular markers.

<p>Top: six different classes of brain tumor patients were tested for their immunosignature. We examined <i>Glioblastoma multiformae</i> (MGMT- is brown, MGMT+ is purple), astrocytoma grade II (red), oligodendroglioma (cyan) and mixed oligo/astro (blue) against otherwise healthy controls (yellow). We used a 1-way ANOVA to select the 100 most significant peptides, p<10⁻¹⁸. High (red) and low (blue) signals correspond to patient antibodies detected with a fluorescently labeled anti-human secondary. Data was grouped using hierarchical clustering on both peptides (Y-axis) and patients (X-axis). Bottom right: principal components display of the separation between samples. X and Y axes represent the first two principal components making up 64% of the total variance across the samples. Patient information is found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040201#pone-0040201-t001" target="_blank">Table 1</a>.</p

Patient information and classification performance.

a<p> = GBMs in which the MGMT promoter is methylated.</p>b<p> =  GBMs in which the MGMT promoter is not methylated.</p>c<p> =  Total number of patients with each diagnosis.</p>d<p> =  number of males and females tested and median age±standard deviation.</p>e<p> =  classification specificity of that tumor type vs. control.</p>f<p> =  classification sensitivity of that tumor type vs. control.</p>g<p> =  classification accuracy of that tumor type vs. control using LDA and LOOCV.</p>h<p> =  area under the ROC (Receiver Operator Characteristic) curve.</p

Classification across diseases.

<p>The heatmap presented here distinguishes 4 different diseases using 70 peptides identified as the most significant using a 1-way ANOVA across the 27 breast cancer patients, 19 healthy controls, 10 <i>Gliobastoma multiformae</i> patients, and 9 Valley Fever patients. Classification accuracy was 100% using both linear discriminant analysis and Support Vector Machines and leave one out cross-validation.</p

Glioblastoma training and test data.

<p>The heatmap on the left shows 50 peptides that differentiated glioblastoma patients from healthy persons obtained from 4 different geographical locations across the US (Fred Hutchison Institute, University of Washington, University of California Irvine, Arizona State University). These peptides were also used to classify different samples consisting of blinded patient and healthy sera obtained from the Barrow Neurological Institute 3 years later. The colored bars on the right indicate clusters that define groups of peptides. Although there are differences between the values obtained in 2007 and 2010, most of the high-binding peptides are very similar.</p

Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart

Abstract Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts. Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca2+ homeostasis, increased contractility, and increased the manifestation of arrhythmia markers. These effects could be reversed by late INa inhibitors, ranolazine and GS-967. We also report that atrial tissues from donor hearts affected by atrial fibrillation exhibit arrhythmia markers in the absence of drug treatment and inhibition of late INa with GS-967 leads to a significant reduction in arrhythmic behaviour. These findings reveal a critical role for the late INa in cardiac arrhythmias and suggest that inhibition of this conductance could provide an effective therapeutic strategy. Finally, this study highlights the utility of human ex-vivo heart models for advancing cardiac translational sciences