Citations

Abstract Background: Binding of the human IgM antibody B7-DC XAb to B7-DC on dendritic cells (DC) has profound immune modulatory effects. It enhances antigen presentation by DC, repolarizes T-helper (Th) 2 to Th1 cell responses, rapidly generates cytotoxic effectors and reprograms regulatory T-cells (Treg) into non-suppressive, cytokine producing autoimmune effectors. We hypothesized that co-culture of B7-DC XAb treated DC (DCXAb) with Treg results in the rapid generation of cytotoxic effectors. Methods: Bone marrow derived DC from wild type C57BL6 mice (WT-B6) were treated for 24 hours with either B7-DC XAb or a control human IgM antibody in the presence of melanoma cell lysate (B16). Subsequently, DCXAb were co-cultured with Treg (CD4+CD25+FOXP3+), Non-Treg (CD4+, CD25-), cytotoxic CD8+ T-cells isolated from WT-B6 mice and Treg from CD8 knockout mice (CD8 -/-). After re-isolation these T-cells were used in cytotoxic T-lymphocyte (CTL) assays targeting B16 and Thymic lymphoma (EL4) tumor cells. Results: Treg isolated from either WT-B6 mice or CD8 -/- mice co-cultured with B16 lysate treated DCXAb but not control antibody treated DC transformed into cytotoxic effectors targeting B16 but not EL4 tumor cells. Their level of cytotoxicity was comparable to that of CD8+ cells co-cultured with DCXAb. In contrast Non-Treg co-cultured with DCXAb did not kill in similar CTL assays. Conclusion: Co-culture of Treg with antigen treated DCXAb rapidly generates antigen specific cytotoxic effectors.

AbstractBackgroundAlzheimer’s disease (AD) lacks a fast, easy, reliable, and inexpensive method of diagnosis. Currently, diagnosis is based on time‐consuming behavioral tests and the exclusion of other potential causes of impairment. Several biomarkers show good or promising diagnostic performance (e.g. CSF, tau PET, MRI, blood), but are either expensive, invasive, or still in development and while some can detect preclinical disease stages, all appear slow to change relative to the rate of cognitive decline. Here we develop a prototype diagnostic classifier based on novel metrics of brain activity in resting state electroencephalography (EEG) that correlates well with mental status.MethodArchival resting‐state EEG recordings of older adults (N=248) came from a memory clinic and university‐based clinic with a range of clinical diagnoses including subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and dementia, representing AD, vascular dementia, and Lewy body dementia, TBI, and depression. We developed XGBoost classifiers to detect AD using EEG, age, and sex under increasingly challenging conditions. We computed metrics of periodic and aperiodic brain activity using the FOOOF algorithm. Furthermore, we developed a novel technique called [Banded Fractal Variability], which yields a set of features based on fluctuations in the fractal dimension within canonical frequency bands. We trained classifiers using cross‐validation to avoid overfitting during hyperparameter selection.ResultAlong with ROCAUC, we report an optimal sensitivity, specificity, and accuracy for the point on the ROC curve that maximizes Youden’s j. The classification tasks were healthy vs. probable AD (ROCAUC = 98%, sensitivity = 90%, specificity = 99%, accuracy = 96%), SCI vs. mild AD (ROCAUC = 89%, sensitivity = 76%, specificity = 87%, accuracy = 84%), and AD vs. other pathologies (no AD diagnosis) in MCI and dementia patients (ROCAUC = 82%, sensitivity = 72%, specificity = 87%, accuracy = 80%). All ROCAUC values were stronger than would be expected by chance (ps < 0.001).ConclusionThese preliminary results suggest that AD could be diagnosed in the clinic on the basis of machine‐learning classifiers and resting‐state EEG. Furthermore, they demonstrate that [Banded Fractal Variability] carries clinically‐relevant information about AD.

AbstractIntravascular volume is largely regulated by the kidneys but how differences in intravascular volume profiles interact with chronic kidney disease (CKD) to influence outcomes in chronic heart failure (HF) has not been explored. Our hypothesis was that a greater degree of volume expansion (VE) would moderate the impact of CKD on HF‐related clinical outcomes. Quantitative blood volume (BV) data were available in 137 patients at the time of hospital discharge using a nuclear medicine radiolabeled albumin indicator‐dilution technique. The study patients were stratified by the cohort median glomerular filtration rate (GFR, 44 ml/min/1.73 m2). An a priori cut‐point of ≥+25% above normal BV was then used to further stratify the two GFR subgroups and prospectively analyzed for 1‐year HF‐related mortality or 1st re‐hospitalization. Persistent BV expansions ≥+25% were present in 51% of the cohort. In the subgroup with GFR above the median (N = 68) greater or lesser BV expansion from +25% did not differentiate outcomes. However, in the subgroup with GFR below the median (N = 69), BV expansion‐stratified risk (log‐rank p = 0.022) with <+25% VE associated with poorer outcomes, while VE ≥ + 25% was associated with lower risk and comparable to GFR above the median. In patients with chronic HF, significant intravascular VE and CKD are common co‐existing conditions. The presence of larger VE, however, appears to be a factor mitigating the impact of declining renal function on clinical outcomes, and as an element of volume pathophysiology warrants further study.