An inducible transgenic mouse breast cancer model for the analysis of tumor antigen specific CD8+ T-cell responses

In Simian virus 40 (SV40) transgenic BALB/c WAP-T mice tumor development and progression is driven by SV40 tumor antigens encoded by inducible transgenes. WAP-T mice constitute a well characterized mouse model for breast cancer with strong similarities to the corresponding human disease. BALB/c mice mount only a weak cellular immune response against SV40 T-antigen (T-Ag). For studying tumor antigen specific CD8⁺ T-cell responses against transgene expressing cells, we created WAP-T_NP mice, in which the transgene additionally codes for the NP_118–126-epitope contained within the nucleoprotein of lymphocytic choriomeningitis virus (LCMV), the immune-dominant T-cell epitope in BALB/c mice. We then investigated in WAP-T_NP mice the immune responses against SV40 tumor antigens and the NP-epitope within the chimeric T-Ag/NP protein (T-Ag_NP). Analysis of the immune-reactivity against T-Ag in WAP-T and of T-Ag_NP in WAP-T_NP mice revealed that, in contrast to wild type (wt) BALB/c mice, WAP-T and WAP-T_NP mice were non-reactive against T-Ag. However, like wtBALB/c mice, WAP-T as well as WAP-T_NP mice were highly reactive against the immune-dominant LCMV NP-epitope, thereby allowing the analysis of NP-epitope specific cellular immune responses in WAP-T_NP mice. LCMV infection of WAP-T_NP mice induced a strong, LCMV NP-epitope specific CD8⁺ T-cell response, which was able to specifically eliminate T-Ag_NP expressing mammary epithelial cells both prior to tumor formation (i.e. in cells of lactating mammary glands), as well as in invasive tumors. Elimination of tumor cells, however, was only transient, even after repeated LCMV infections. Further studies showed that already non-infected WAP-T_NP tumor mice contained LCMV NP-epitope specific CD8⁺ T-cells, albeit with strongly reduced, though measurable activity. Functional impairment of these ‘endogenous’ NP-epitope specific T-cells seems to be caused by expression of the programmed death-1 protein (PD1), as anti-PD1 treatment of splenocytes from WAP-T_NP tumor mice restored their activity. These characteristics are similar to those found in many tumor patients and render WAP-T_NP mice a suitable model for analyzing parameters to overcome the blockade of immune checkpoints in tumor patients.     

The difficult balance between thrombosis and bleeding after transcatheter aortic valve replacement: A translational review

The difficult balance between thrombosis and bleeding after transcatheter aortic valve replacement. TAVR: transcatheter aortic valve replacement.

     

Effects of a synbiotic on symptoms,and daily functioning in attention deficit hyperactivity disorder – A double-blind randomized controlled trial

Some prebiotics and probiotics have been proposed to improve psychiatric symptoms in children with autism. However, few studies were placebo-controlled, and there is no study on persons with an attention deficit hyperactivity disorder (ADHD) diagnosis. Our aim was to study effects of Synbiotic 2000 on psychiatric symptoms and functioning in children and adults with ADHD without an autism diagnosis. Children and adults (n = 182) with an ADHD diagnosis completed the nine weeks randomized double-blind parallel placebo-controlled trial examining effects of Synbiotic 2000 on the primary endpoints ADHD symptoms, autism symptoms and daily functioning, and the secondary endpoint emotion regulation, measured using the questionnaires SNAP-IV, ASRS, WFIRS, SCQ, AQ and DERS-16. Levels at baseline of plasma C-reactive protein and soluble vascular cell adhesion molecule-1 (sVCAM-1), central to leukocyte-endothelial cell adhesion facilitating inflammatory responses in tissues, were measured using Meso Scale Discovery. Synbiotic 2000 and placebo improved ADHD symptoms equally well, and neither active treatment nor placebo had any statistically significant effect on functioning or sub-diagnostic autism symptoms. However, Synbiotic 2000, specifically, reduced sub-diagnostic autism symptoms in the domain restricted, repetitive and stereotyped behaviors in children, and improved emotion regulation in the domain of goal-directed behavior in adults. In children with elevated sVCAM-1 levels at baseline as well as in children without ADHD medication, Synbiotic 2000 reduced both the total score of autism symptoms, and the restricted, repetitive and stereotyped behaviors. In adults with elevated sVCAM-1 at baseline, Synbiotic 2000 significantly improved emotion regulation, both the total score and four of the five subdomains. To conclude, while no definite Synbiotic 2000-specific effect was detected, the analysis of those with elevated plasma sVCAM-1 levels proposed a reduction of autism symptoms in children and an improvement of emotion regulation in adults with ADHD.Trial registration number: ISRCTN57795429.     

Local thermal reaction after influenza vaccination: Quantification by infrared imaging and biometric considerations

BackgroundExtensive clinical investigations are mandatory to evaluate the safety and reactogenicity of vaccines. The recording of common adverse events like injection site soreness or general discomfort derives from individual subjective perceptions. Thermal imaging at the injection site possibly provides a non-subjective and a non-invasive approach to supplement this evaluation.ResultsA protocol for quantified injection-site infrared imaging included 86 participants during a flu vaccine campaign, 40% of whom had a thermal reaction of 1 °C; 25–30% had no thermal response. There was little subjective pain reporting and no clinical correlations were observed except with post-vaccination erythema.Higher responses were linked with advanced age and multiple previous vaccinations.ConclusionEvan if influenza vaccine was only moderately reactogenic, a thermal response was detectable in about 70% of vaccinees, though no relationship to reactogenicity was seen.Infrared imaging might however be a prospective tool for individual studies of vaccine-induced vascular responses.     

Deficient processing of alcohol cues in the addicted brain: Evidence from event-related potential microstates

ObjectivePatients with alcohol use disorder (AUD) show altered brain responses to alcohol cues as compared to healthy controls. Event-related potential (ERP) studies mostly focus on the P3, which is usually diminished in AUD patients. The few studies that have investigated earlier components have yielded inconsistent results. The present study aimed at identifying the onset of impaired alcohol cue processing in AUD patients, as well as the association between neurophysiological processing and subjective craving.MethodsA sample of 15 inpatients with AUD and 15 healthy controls completed a cue reactivity task with alcohol-related, neutral, and scrambled pictures. Multichannel-EEG was recorded from 70 scalp electrodes, and ERP microstates were analyzed.ResultsPatients displayed impaired neurophysiological processing, as indexed by a weaker P3 and a weaker, insensitive P1. The blunted P1 was associated with higher subjective craving.ConclusionsImpaired alcohol cue processing in AUD emerges early, at the stage of sensory processing. Such deficient initial processing seems crucial to understanding cue reactivity processes in the brain and in the subjective experience of craving.SignificanceThe results highlight the importance of investigating early ERP components preceding the P3, and contribute to the debate on the onset of information-processing dysfunction in the addicted brain.     

Prediction of skin sensitization potency using machine learning approaches

The replacement of animal use in testing for regulatory classification of skin sensitizers is a priority for US federal agencies that use data from such testing. Machine learning models that classify substances as sensitizers or non‐sensitizers without using animal data have been developed and evaluated. Because some regulatory agencies require that sensitizers be further classified into potency categories, we developed statistical models to predict skin sensitization potency for murine local lymph node assay (LLNA) and human outcomes. Input variables for our models included six physicochemical properties and data from three non‐animal test methods: direct peptide reactivity assay; human cell line activation test; and KeratinoSens™ assay. Models were built to predict three potency categories using four machine learning approaches and were validated using external test sets and leave‐one‐out cross‐validation. A one‐tiered strategy modeled all three categories of response together while a two‐tiered strategy modeled sensitizer/non‐sensitizer responses and then classified the sensitizers as strong or weak sensitizers. The two‐tiered model using the support vector machine with all assay and physicochemical data inputs provided the best performance, yielding accuracy of 88% for prediction of LLNA outcomes (120 substances) and 81% for prediction of human test outcomes (87 substances). The best one‐tiered model predicted LLNA outcomes with 78% accuracy and human outcomes with 75% accuracy. By comparison, the LLNA predicts human potency categories with 69% accuracy (60 of 87 substances correctly categorized). These results suggest that computational models using non‐animal methods may provide valuable information for assessing skin sensitization potency. Copyright © 2017 John Wiley & Sons, Ltd.